TW202128653A - Pyridazinones as parp7 inhibitors - Google Patents

Abstract

The present invention relates to pyridazinones and related compounds which are inhibitors of PARP7 and are useful in the treatment of cancer.

Description

Ta ketone as a PARP7 inhibitor

The present invention relates to ketone and related compounds that are inhibitors of PARP7 and can be used to treat cancer.

Poly(ADP-ribose) polymerase (PARP) is a member of the 17 enzyme family that regulates basic cellular processes, including gene expression, protein degradation, and various cellular stress responses (MS Cohen, P. Chang, Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat Chem Biol 14, 236-243 (2018)). The ability of cancer cells to survive under stress is the basic cancer mechanism and emerging methods of novel therapeutic agents. PARP1, a member of the PARP family, has been shown to be an effective cancer target related to cellular stress induced by DNA damage, which is induced by genetic mutations or cytotoxic chemotherapy, using four approved drugs in the clinic and developing at an advanced stage Several other drugs are used (A. Ohmoto, S. Yachida, Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther 10, 5195-5208 (2017)).

Based on the homology within the catalytic domain, 17 members of the PARP family were identified in the human genome (S. Vyas, M. Chesarone-Cataldo, T. Todorova, YH Huang, P. Chang, A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. Nat Commun 4, 2240 (2013)). However, its catalytic activity belongs to 3 different categories (S. Vyas et al., Family-wide analysis of poly(ADP-ribose) polymerase activity. Nat Commun 5, 4426 (2014)). Most PARP family members catalyze the transfer of mono-ADP-ribose units to their substrate (mono-PARP), while other PARP family members (PARP1, PARP2, TNKS2) catalyze the transfer of poly-ADP-ribose units to the substrate (poly PARP). Finally, PARP13 is the only PARP that has not been able to exhibit its catalytic activity in vitro or in vivo.

Aromatic hydrocarbon receptor (AHR) is a transcription factor involved in the regulation of ligand activation for a variety of cellular functions, including pro-inflammatory response and heterogeneous biomass metabolism (S. Feng, Z. Cao, X. Wang, Role of aryl hydrocarbon receptor in cancer. Biochim Biophys Acta 1836, 197-210 (2013); and B. Stockinger, P. Di Meglio, M. Gialitakis, JH Duarte, The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol 32 , 403-432 (2014)). AHR can be activated by a variety of ligands, including endogenous tryptophan metabolites, such as kynurenine (CA Opitz et al ., An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197- 203 (2011)) and certain polycyclic aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated (TCDD) (KW Bock, Toward elucidation of dioxin-mediated chloracne and Ah receptor functions. Biochem Pharmacol 112, 1-5 (2016)). The activation of AHR induces the expression of target genes, including genes involved in metabolism, such as cytochrome P4501A1 and P4501B1. The activation of AHR also leads to an increase in AHR target genes, TCDD inducible poly(ADP-ribose) polymerase (TIPARP, also known as PARP7), which acts as a negative regulator of certain AHR transcription targets (L. MacPherson Et al., Aryl hydrocarbon receptor repressor and TIPARP (ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. Int J Mol Sci 15, 7939-7957 (2014); and L. MacPherson et al ., 2, 3, 7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TIPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res 41, 1604-1621 (2013)).

PARP7 can also be regulated by other transcription factors and signal transduction pathways, including androgen receptor (EC Bolton et al., Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21, 2005-2017 (2007)) , Platelet-derived growth factor (J. Schmahl, CS Raymond, P. Soriano, PDGF signaling specificity is mediated through multiple immediate early genes. Nat Genet 39, 52-60 (2007)) and hypoxia inducible factor 1 (N. Hao et al., Xenobiotics and loss of cell adhesion drive distinct transcriptional outcomes by aryl hydrocarbon receptor signaling. Mol Pharmacol 82, 1082-1093 (2012)). The PARP7 gene is located on chromosome 3 (3q25) (http://www.cbioportal.org/index.do?session_id=5ae1bcde498eb8b3d565d8b2) in the region usually amplified in cancers of squamous histology. Genome-wide association studies identified 3q25 as a susceptibility locus for ovarian cancer, indicating the role of PARP7 in this cancer type (ELGoode et al., A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat Genet 42, 874-879 (2010)). PARP7 has a variety of cellular functions. In the context of AHR signaling, PARP7 acts as a negative feedback mechanism to regulate the performance of P4501A1 and P4501B1 (L. MacPherson et al., Aryl hydrocarbon receptor repressor and TIPARP (ARTD14) use similar, but also distinct mechanisms to repress aryl hydrocarbon receptor signaling. Int J Mol Sci 15, 7939-7957 (2014), and L. MacPherson et al ., 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TIPARP, ARTD14) is a mono-ADP- ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation. Nucleic Acids Res 41, 1604-1621 (2013)). It has also been described that PARP7 can ADP-ribosylates the liver X receptor, which leads to the regulation of its transcriptional activity (C. Bindesboll et al ., TCDD-inducible poly-ADP-ribose polymerase (TIPARP/PARP7) mono-ADP-ribosylates and co -activates liver X receptors. Biochem J 473, 899-910 (2016). During viral infection, PARP7 can bind to Sindbis virus (SINV) to promote viral RNA degradation (T. Kozaki et al., Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response. Proc Natl Acad Sci USA 114, 2681-2686 (2017)). Also in the context of viral infection, AHR-induced PARP7 can interact with TBK1 TBK1 is a major kinase that is activated during the initiation of pathogen-associated molecular model pathways to cause type I interferon response and activation of antiviral immunity (T. Yamada et al., Constitutive aryl hydrocarbon receptor signaling constrains Type I interferon-mediated antiviral innate defense. Nat Immunol 17, 687-694 (2016)). It was shown that PARP7 can ADP-ribosylate TBK1, which prevents its activation, thereby inhibiting the type I interferon response.

Based on these results of viral infection, it can be assumed that cancer cells can use abnormally behaved and/or activated PARP7 as a means of evading the host immune system by suppressing type I interferon and thereby suppressing T cell-mediated anti-tumor immunity. mechanism. In fact, in a recent genetic screen to identify tumor factors that inhibit T cell activation, PARP7 was identified as a hit (D. Pan et al., A major chromatin regulator determines resistance of tumor cells to T cell- mediated killing. Science 359, 770-775 (2018)). PARP7 knock-out in mouse melanoma cell lines showed increased proliferation and activation of co-cultured T cells, indicating that PARP7 inhibition may be a feasible strategy for tumor killing mediated by activated T cells. Therefore, there is a continuing need to develop PARP7 inhibitors.

I 或其醫藥上可接受之鹽，其中下文定義組成成員。The present invention relates to compounds of formula I:

I or a pharmaceutically acceptable salt thereof, wherein the constituent members are defined below.

The present invention further relates to a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

The present invention further relates to a method for inhibiting the activity of PARP7, which comprises contacting a compound of formula I or a pharmaceutically acceptable salt thereof with PARP7.

The present invention further relates to a method for treating a disease or disorder in a patient in need of treatment, wherein the disease or disorder is characterized by PARP7 overexpression or increased activity, and the method comprises administering to the patient a therapeutically effective amount of a compound of formula I or its medicine The acceptable salt.

The present invention further relates to a method of treating cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an agent that inhibits the activity of PARP7, such as a compound of formula I or a pharmaceutically acceptable salt thereof. The present disclosure also provides the use of the compounds described herein in the manufacture of medicaments for use in therapy. The disclosure also provides the compounds described herein for use in therapy.

I 或其醫藥上可接受之鹽，其中： X係Cl、Br、F、CH₃ 、CF₃ 、CF₂ H、CN、OCH₃ 、乙基、環丙基、SCH₃ 或異丙基； A係具有為(A-1)之式之基團：

(A-1) Y¹ 、Y² 及Y³ 各自獨立地選自O、S、NR^Y 、C(=O)、C(=O)O、C(=O)NR^Y 、S(=O)、S(=O)₂ 、S(=O)NR^Y 、S(=O)₂ NR^Y 或NR^Y C(=O)NR^Y ，其中各R^Y 獨立地係H、C_1-4 烷基或C_1-4 鹵烷基； L係C_1-3 伸烷基、O、S、NR^Y 、C(=O)、C(=O)O、C(=O)NR^Y 、S(=O)、S(=O)NR^Y 或NR^Y C(=O)NR^Y ； Z係H、Cy^Z 、鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a 、SR^a 、C(O)R^b 、C(O)NR^c R^d 、C(O)OR^a 、OC(O)R^b 、OC(O)NR^c R^d 、NR^c R^d 、NR^c C(O)R^b 、NR^c C(O)OR^a 、NR^c C(O)NR^c R^d 、C(=NR^e )R^b 、C(=NR^e )NR^c R^d 、NR^c C(=NR^e )NR^c R^d 、NR^c S(O)R^b 、NR^c S(O)₂ R^b 、NR^c S(O)₂ NR^c R^d 、S(O)R^b 、S(O)NR^c R^d 、S(O)₂ R^b 及S(O)₂ NR^c R^d ；其中Z之該等C_1-6 烷基、C_2-6 烯基、C_2-6 炔基及C_1-6 鹵烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：Cy^Z 、鹵基、CN、NO₂ 、OR^a 、SR^a 、C(O)R^b 、C(O)NR^c R^d 、C(O)OR^a 、OC(O)R^b 、OC(O)NR^c R^d 、C(=NR^e )NR^c R^d 、NR^c C(=NR^e )NR^c R^d 、NR^c R^d 、NR^c C(O)R^b 、NR^c C(O)OR^a 、NR^c C(O)NR^c R^d 、NR^c S(O)R^b 、NR^c S(O)₂ R^b 、NR^c S(O)₂ NR^c R^d 、S(O)R^b 、S(O)NR^c R^d 、S(O)₂ R^b 及S(O)₂ NR^c R^d ； Cy^Z 選自C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基及4-10員雜環烷基，其各自視情況由1、2、3或4個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、C(=NR^e1 )NR^c1 R^d1 、NR^c1 C(=NR^e1 )NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)OR^a1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 S(O)R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 及S(O)₂ NR^c1 R^d1 ，其中該等烷基、C_2-6 烯基及C_2-6 炔基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、NO₂ 、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、C(=NR^e1 )NR^c1 R^d1 、NR^c1 C(=NR^e1 )NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)OR^a1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 S(O)R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 及S(O)₂ NR^c1 R^d1 ； 環D係單環或多環4-10員雜環烷基，其視情況經1、2或3個獨立地選自以下之基團取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a2 、SR^a2 、C(O)R^b2 、C(O)NR^c2 R^d2 、C(O)OR^a2 、OC(O)R^b2 、OC(O)NR^c2 R^d2 、C(=NR^e2 )NR^c2 R^d2 、NR^c2 C(=NR^e2 )NR^c2 R^d2 、NR^c2 R^d2 、NR^c2 C(O)R^b2 、NR^c2 C(O)OR^a2 、NR^c2 C(O)NR^c2 R^d2 、NR^c2 S(O)R^b2 、NR^c2 S(O)₂ R^b2 、NR^c2 S(O)₂ NR^c2 R^d2 、S(O)R^b2 、S(O)NR^c2 R^d2 、S(O)₂ R^b2 及S(O)₂ NR^c2 R^d2 ，其中該等C_1-6 烷基、C_2-6 烯基及C_2-6 炔基各自視情況經1、2或3個獨立地選自以下之基團取代：鹵基、CN、NO₂ 、OR^a2 、SR^a2 、C(O)R^b2 、C(O)NR^c2 R^d2 、C(O)OR^a2 、OC(O)R^b2 、OC(O)NR^c2 R^d2 、C(=NR^e2 )NR^c2 R^d2 、NR^c2 C(=NR^e2 )NR^c2 R^d2 、NR^c2 R^d2 、NR^c2 C(O)R^b2 、NR^c2 C(O)OR^a2 、NR^c2 C(O)NR^c2 R^d2 、NR^c2 S(O)R^b2 、NR^c2 S(O)₂ R^b2 、NR^c2 S(O)₂ NR^c2 R^d2 、S(O)R^b2 、S(O)NR^c2 R^d2 、S(O)₂ R^b2 及S(O)₂ NR^c2 R^d2 ； R¹ 、R² 、R³ 、R⁴ 、R⁵ 、R⁶ 、R⁷ 、R⁸ 、R⁹ 、R¹⁰ 、R¹¹ 及R¹² 各自獨立地選自H、鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基、4-10員雜環烷基-C_1-4 烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ；其中該等R¹ 、R² 、R³ 、R⁴ 、R⁵ 、R⁶ 、R⁷ 、R⁸ 、R⁹ 、R¹⁰ 、R¹¹ 及R¹² 之該等C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基及4-10員雜環烷基-C_1-4 烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 或R¹ 及Y¹ 之R^Y 基團與其連接之原子一起及與形成Y¹ 之原子一起形成4-10員雜環烷基環，其視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 或R⁷ 及Y³ 之R^Y 基團與其連接之原子一起及與形成Y³ 之原子一起及與由R⁹ 、R¹⁰ 、R¹¹ 及R¹² 取代之碳原子(若存在)一起形成4-10員雜環烷基環，其視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 或R¹ 及R³ 與其連接之碳原子一起形成C_5-10 環烷基環或5-10員雜環烷基環，其各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 或R³ 及R⁵ 與其連接之碳原子一起形成C_5-10 環烷基環或5-10員雜環烷基環，其各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 或R⁷ 及R⁹ 與其連接之碳原子一起形成C_5-10 環烷基環或5-10員雜環烷基環，其各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 或R⁹ 及R¹¹ 與其連接之碳原子一起形成C_5-10 環烷基環或5-10員雜環烷基環，其各自視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 或R⁵ 及R⁷ 與其連接之碳原子一起及與Y² 一起形成5-10員雜環烷基環，其視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 或R¹ 及R³ 在與其連接之碳原子之間一起形成雙鍵； 或R³ 及R⁵ 在與其連接之碳原子之間一起形成雙鍵； 或R⁷ 及R⁹ 在與其連接之碳原子之間一起形成雙鍵； 或R⁹ 及R¹¹ 在與其連接之碳原子之間一起形成雙鍵； 或R⁹ 、R¹⁰ 、R¹¹ 及R¹² 在與其連接之碳原子之間一起形成三鍵； 各R^a 、R^b 、R^c 、R^d 、R^a1 、R^b1 、R^c1 、R^d1 、R^a2 、R^b2 、R^c2 、R^d2 、R^a3 、R^b3 、R^c3 及R^d3 獨立地選自H、C_1-6 烷基、C_1-6 鹵烷基、C_2-6 烯基、C_2-6 炔基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基及4-10員雜環烷基-C_1-4 烷基，其中該等R^a 、R^b 、R^c 、R^d 、R^a1 、R^b1 、R^c1 、R^d1 、R^a2 、R^b2 、R^c2 、R^d2 、R^a3 、R^b3 、R^c3 及R^d3 之該等C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基及4-10員雜環烷基-C_1-4 烷基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-4 烷基、C_1-4 鹵烷基、C_2-6 烯基、C_2-6 炔基、CN、OR^a7 、SR^a7 、C(O)R^b7 、C(O)NR^c7 R^d7 、C(O)OR^a7 、OC(O)R^b7 、OC(O)NR^c7 R^d7 、NR^c7 R^d7 、NR^c7 C(O)R^b7 、NR^c7 C(O)NR^c7 R^d7 、NR^c7 C(O)OR^a7 、C(=NR^e7 )NR^c7 R^d7 、NR^c7 C(=NR^e7 )NR^c3 R^d7 、S(O)R^b7 、S(O)NR^c7 R^d7 、S(O)₂ R^b7 、NR^c7 S(O)₂ R^b7 、NR^c7 S(O)₂ NR^c7 R^d7 及S(O)₂ NR^c7 R^d7 ； 或R^c 及R^d 與其連接之N原子一起形成4-7員雜環烷基，其視情況經1、2或3個獨立地選自以下之取代基取代：CN、鹵基、C_1-4 烷基、C_1-4 鹵烷基、C_1-6 鹵烷基、C_2-6 烯基、C_2-6 炔基、CN、OR^a7 、SR^a7 、C(O)R^b7 、C(O)NR^c7 R^d7 、C(O)OR^a7 、OC(O)R^b7 、OC(O)NR^c7 R^d7 、NR^c7 R^d7 、NR^c7 C(O)R^b7 、NR^c7 C(O)NR^c7 R^d7 、NR^c7 C(O)OR^a7 、C(=NR^e7 )NR^c7 R^d7 、NR^c7 C(=NR^e7 )NR^c3 R^d7 、S(O)R^b7 、S(O)NR^c7 R^d7 、S(O)₂ R^b7 、NR^c7 S(O)₂ R^b7 、NR^c7 S(O)₂ NR^c7 R^d7 及S(O)₂ NR^c7 R^d7 ； 或R^c1 及R^d2 與其連接之N原子一起形成4-7員雜環烷基，其視情況經1、2或3個獨立地選自以下之取代基取代：CN、鹵基、C_1-4 烷基、C_1-4 鹵烷基、C_1-6 鹵烷基、C_2-6 烯基、C_2-6 炔基、CN、OR^a7 、SR^a7 、C(O)R^b7 、C(O)NR^c7 R^d7 、C(O)OR^a7 、OC(O)R^b7 、OC(O)NR^c7 R^d7 、NR^c7 R^d7 、NR^c7 C(O)R^b7 、NR^c7 C(O)NR^c7 R^d7 、NR^c7 C(O)OR^a7 、C(=NR^e7 )NR^c7 R^d7 、NR^c7 C(=NR^e7 )NR^c3 R^d7 、S(O)R^b7 、S(O)NR^c7 R^d7 、S(O)₂ R^b7 、NR^c7 S(O)₂ R^b7 、NR^c7 S(O)₂ NR^c7 R^d7 及S(O)₂ NR^c7 R^d7 ； 或R^c2 及R^d2 與其連接之N原子一起形成4-7員雜環烷基，其視情況經1、2或3個獨立地選自以下之取代基取代：CN、鹵基、C_1-4 烷基、C_1-4 鹵烷基、C_1-6 鹵烷基、C_2-6 烯基、C_2-6 炔基、CN、OR^a7 、SR^a7 、C(O)R^b7 、C(O)NR^c7 R^d7 、C(O)OR^a7 、OC(O)R^b7 、OC(O)NR^c7 R^d7 、NR^c7 R^d7 、NR^c7 C(O)R^b7 、NR^c7 C(O)NR^c7 R^d7 、NR^c7 C(O)OR^a7 、C(=NR^e7 )NR^c7 R^d7 、NR^c7 C(=NR^e7 )NR^c3 R^d7 、S(O)R^b7 、S(O)NR^c7 R^d7 、S(O)₂ R^b7 、NR^c7 S(O)₂ R^b7 、NR^c7 S(O)₂ NR^c7 R^d7 及S(O)₂ NR^c7 R^d7 ； 或R^c3 及R^d3 與其連接之N原子一起形成4-7員雜環烷基，其視情況經1、2或3個獨立地選自以下之取代基取代：CN、鹵基、C_1-4 烷基、C_1-4 鹵烷基、C_1-6 鹵烷基、C_2-6 烯基、C_2-6 炔基、CN、OR^a7 、SR^a7 、C(O)R^b7 、C(O)NR^c7 R^d7 、C(O)OR^a7 、OC(O)R^b7 、OC(O)NR^c7 R^d7 、NR^c7 R^d7 、NR^c7 C(O)R^b7 、NR^c7 C(O)NR^c7 R^d7 、NR^c7 C(O)OR^a7 、C(=NR^e7 )NR^c7 R^d7 、NR^c7 C(=NR^e7 )NR^c3 R^d7 、S(O)R^b7 、S(O)NR^c7 R^d7 、S(O)₂ R^b7 、NR^c7 S(O)₂ R^b7 、NR^c7 S(O)₂ NR^c7 R^d7 及S(O)₂ NR^c7 R^d7 ； R^a7 、R^b7 、R^c7 及R^d7 獨立地選自H、C_1-6 烷基、C_1-6 鹵烷基、C_2-6 烯基、C_2-6 炔基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基及4-10員雜環烷基-C_1-4 烷基，其中該等C_1-6 烷基、C_1-6 鹵烷基、C_2-6 烯基、C_2-6 炔基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基及4-10員雜環烷基-C_1-4 烷基各自視情況經1、2或3個獨立地選自以下之取代基取代：OH、CN、胺基、鹵基、C_1-6 烷基、C_1-6 烷氧基、C_1-6 鹵烷基及C_1-6 鹵烷氧基； 各R^e 、R^e1 、R^e2 、R^e3 及R^e7 獨立地選自H、C_1-4 烷基及CN； a係0或1； m係0或1； n係0或1； p係0或1； q係0或1； r係0或1； 其中任何上文所提及之雜芳基或雜環烷基包含1、2、3或4個獨立地選自O、N及S之成環雜原子；且 其中任何上文所提及之雜環烷基之一或多個成環C或N原子視情況由1或2個側氧基(=O)基團取代。The present invention relates to compounds of formula I:

I or a pharmaceutically acceptable salt thereof, wherein: X is Cl, Br, F, CH ₃ , CF ₃ , CF ₂ H, CN, OCH ₃ , ethyl, cyclopropyl, SCH ₃ or isopropyl; A Is a group having the formula (A-1):

(A-1) Y ¹ , Y ² and Y ³ are each independently selected from O, S, NR ^Y , C(=O), C(=O)O, C(=O)NR ^Y , S(=O ), S(=O) ₂ , S(=O)NR ^Y , S(=O) ₂ NR ^Y or NR ^Y C(=O)NR ^Y , where each R ^{Y is} independently H, C _1-4 alkane Group or C _1-4 haloalkyl; L is C _1-3 alkylene, O, S, NR ^Y , C(=O), C(=O)O, C(=O)NR ^Y , S( =O), S(=O)NR ^Y or NR ^Y C(=O)NR ^Y ; Z is H, Cy ^Z , halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C(O)R ^b , C(O)NR ^c R ^d , C(O)OR ^a , OC(O)R ^b , OC(O)NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c C(O)OR ^a , NR ^c C(O)NR ^c R ^d , C(=NR ^e )R ^b , C(=NR ^e )NR ^c R ^d , NR ^c C(=NR ^e )NR ^c R ^d , NR ^c S(O)R ^b , NR ^c S(O) ₂ R ^b , NR ^c S (O) ₂ NR ^c R ^d , S(O)R ^b , S(O)NR ^c R ^d , S(O) ₂ R ^b and S(O) ₂ NR ^c R ^d ; among them, the C _{1 of Z Each of -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl and C _1-6 haloalkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: Cy ^Z , halo, CN, NO ₂ , OR ^a , SR ^a , C(O)R ^b , C(O)NR ^c R ^d , C(O)OR ^a , OC(O)R ^b , OC(O )NR ^c R ^d , C(=NR ^e )NR ^c R ^d , NR ^c C(=NR ^e )NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c C(O) OR ^a , NR ^c C(O)NR ^c R ^d , NR ^c S(O)R ^b , NR ^c S(O) ₂ R ^b , NR ^c S(O) ₂ NR ^c R ^d , S(O)R ^b , S(O)NR ^c R ^d , S(O) ₂ R ^b and S(O) ₂ NR ^c R ^d ; Cy ^{Z is} selected from C _6-10 aryl, C _3-7 cycloalkyl, 5- A 10-membered heteroaryl group and a 4-10 membered heterocycloalkyl group are each substituted with 1, 2, 3, or 4 substituents independently selected from the following as appropriate: Halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 , wherein the alkyl, C _2-6 alkenyl and C _2-6 alkynyl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, CN, NO ₂ , OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; Ring D is a monocyclic or polycyclic 4-10 membered heterocycloalkyl group, which is independently selected from 1, 2 or 3 as appropriate Substitution of the following groups: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C (O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O )NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 , wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl groups may be subjected to 1, Substitution with 2 or 3 groups independently selected from the following: halo, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C( O) R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 Aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl, 4-10 membered heterocycloalkyl-C _1-4 Alkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O )NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C (=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; where these R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² such C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Haloalkyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl and 4-10 membered heterocycloalkyl-C _1-4 alkyl are each as appropriate. , 2, 3, 4 or 5 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl , CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 ) NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 ) NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S (O) R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or the R ^{Y groups of R 1} and Y ¹ together with the atoms to which they are connected and Together with ^{the atom forming Y 1} to form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O )OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are connected and together with ^{the atoms forming Y 3} and together with R ⁹ , R ¹⁰ , R ¹¹ and The carbon atoms substituted by R ¹² (if any) together form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkane Group, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C (O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ¹ and R ³ together with the carbon atoms to which they are connected form a C _5-10 cycloalkyl ring or a 5-10 membered heterocycloalkyl ring, each of which may be separated by 1, 2 or 3 as appropriate Substituent substitutions selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C( O) R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(= NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O) N R ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ³ and R ⁵ together with the carbon atom to which they are connected form a C _5-10 cycloalkyl ring or a 5-10 membered hetero Cycloalkyl rings, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC (O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or the carbon to which ^{R 7} and R ^{9 are connected} The atoms together form a C _5-10 cycloalkyl ring or a 5-10 membered heterocycloalkyl ring, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ) ₂ NR ^c3 R ^d3 ; or R ⁹ and R ¹¹ together with the carbon atoms to which they are connected form a C _5-10 cycloalkyl ring or a 5-10 membered heterocycloalkyl ring, each of which has 1, 2, or 3 as appropriate Substituents substituted independently selected from the following ：Halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C (O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O ) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ⁵ and R ⁷ together with the carbon atom to which they are connected and together with Y ² form a 5- to 10-membered heterocycloalkyl ring, which is subject to 1, 2 Or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ¹ and R ³ together form a double bond between the carbon atoms to which they are connected; or R ³ and R ⁵ forms a double bond between the carbon atoms to which it is connected; or R ⁷ and R ⁹ form a double bond between the carbon atoms to which they are connected; or R ⁹ and R ¹¹ form a double bond between the carbon atoms to which they are connected a double bond; or R ^9, R ^10, R ¹¹ and R ¹² together form a triple bond between the carbon atoms connected thereto; each ^{R a, R b, R c} , R d, R a1, R b1, R c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 , R ^d2 , R ^a3 , R ^b3 , R ^c3 and ^{Rd3 are} independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl -C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl and 4-10 membered heterocycloalkyl-C _{1- 4} alkyl group, those wherein ^{R a, R b, R c} , R d, R a1, R b1, R c1, R d1, R a2, R b2, R c2, R d2, R a3, R b3, R ^The C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl groups of c3 and R ^d3 , 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _{1- The 4-} alkyl group and 4-10 membered heterocycloalkyl-C _1-4 alkyl group are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-4 alkyl, C _{1 -4} haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O)NR ^c7 R ^d7 , C(O)OR ^a7 , OC(O)R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)NR ^c7 R ^d7 , NR ^c7 C(O)OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; or R ^c and R ^d together with the N atom to which they are connected to form a 4-7 membered heterocyclic ring Alkyl group, optionally substituted with 1, 2 or 3 substituents independently selected from the following: CN, halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-6 haloalkyl , C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O)NR ^c7 R ^d7 , C(O)OR ^a7 , OC(O) R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)NR ^c7 R ^d7 , NR ^c7 C(O)OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; or R ^c1 and R ^d2 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: CN, halo, C _1-4 Alkyl, C _1-4 haloalkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C( O)NR ^c7 R ^d7 , C(O)OR ^a7 , OC(O)R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O) NR ^c7 R ^d7 , NR ^c7 C(O)OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; or R ^c2 and ^Rd2 Together with the N atom to which it is attached, a 4-7 membered heterocycloalkyl group is formed, which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: CN, halo, C _1-4 alkyl, C _{1 -4} haloalkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O)NR ^c7 R ^d7 , C(O)OR ^a7 , OC(O)R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)NR ^c7 R ^d7 , NR ^c7 C(O)OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S (O) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; or R ^c3 and R ^d3 together with the N atom to which they are attached form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: CN, halo, C _1-4 alkane Group, C _1-4 haloalkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O )NR ^c7 R ^d7 , C(O)OR ^a7 , OC(O)R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)NR ^c7 R ^d7 , NR ^c7 C(O)OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; R ^a7 , R ^b7 , R ^c7 and R ^{d7 are} independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl and 4-10 membered heterocycloalkyl-C _1-4 alkyl, wherein these C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl Group-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl and 4-10 membered heterocycloalkyl-C _{1 Each -4} alkyl group is optionally substituted with 1, 2 or 3 substituents independently selected from the following: OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl and C _1-6 haloalkoxy; each of R ^e , R ^e1 , R ^e2 , R ^e3 and R ^{e7 is} independently selected from H, C _1-4 alkyl and CN; a is 0 or 1; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; r is 0 or 1; wherein any of the above-mentioned heteroaryl or heterocycloalkyl includes 1 , 2, 3, or 4 ring-forming heteroatoms independently selected from O, N and S; and one or more of the above-mentioned heterocycloalkyl groups of which one or more ring-forming C or N atoms are selected from 1 Or 2 pendant oxy (=O) groups are substituted.

In some embodiments, X is CF ₃ , Br, or Cl. In some embodiments, X is CF ₃ . In some embodiments, X is Br or Cl. In some embodiments, X is Br. In some embodiments, X is Cl.

In some embodiments, Y ¹ is NR ^Y or O. In some embodiments, Y ¹ is NR ^Y. In some embodiments, Y ¹ is NH. In some embodiments, Y ¹ is O. In some embodiments, Y ¹ is NH or O.

In some embodiments, Y ² is O, NR ^Y or C(=0)NR ^Y. In some embodiments, Y ² is O, NH, NCH ₃ or C(=0)NH. In some embodiments, Y ² is O or NR ^Y. In some embodiments, Y ² is O. In some embodiments, Y ² is NR ^Y. In some embodiments, Y ² is O, NH or NCH ₃ . In some embodiments, Y ² is NH or NCH ₃ . In some embodiments, Y ² is NH. In certain embodiments, Y ² is NCH ₃ .

In some embodiments, Y ³ is C(=0)NR ^Y. In some embodiments, Y ³ is C(=0)NH. In some embodiments, Y ³ is C(=0)NCH ₃ . In some embodiments, Y ³ is C(=0)NCH ₂ . In some embodiments, Y ³ is C(=0)NH or C(=0)NCH ₃ .

In some embodiments, the R ^{Y of Y 1} is H.

In some embodiments, R ^{Y of Y 2} is H or C _1-4 alkyl. In some embodiments, R ^{Y of Y 2} is H or methyl. In some embodiments, the R ^{Y of Y 2} is H. In some embodiments, R ^{Y of Y 2} is a methyl group.

In some embodiments, R ^{Y of Y 3} is H or C _1-4 alkyl. In some embodiments, R ^{Y of Y 3} is H, methyl, or ethyl. In some embodiments, the R ^{Y of Y 3} is H. In some embodiments, R ^{Y of Y 3} is a methyl group. In some embodiments, R ^{Y of Y 3} is ethyl. In some embodiments, R ^{Y of Y 3} is CH ₂ .

In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from H, halo , C _1-6 alkyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; wherein the C _1-6 alkyl group depends on the circumstances Substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: halo, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C (O)NR ^c3 R ^d3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 .

In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from H, halo , C _1-6 alkyl and C _1-6 haloalkyl, wherein the C _1-6 alkyl is optionally substituted with 1 or 2 substituents independently selected from the following: halo, CN, NO ₂ , OR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , S(O) ₂ R ^b3 and S(O) ) ₂ NR ^c3 R ^d3 .

In some embodiments, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from H, halo , C _1-6 alkyl group and C _1-6 haloalkyl group, wherein the C _1-6 alkyl group is optionally substituted ^{by OR a3.}

In some embodiments, R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from H, halo, C _1-6 alkyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; wherein the C _1-6 alkyl group is optionally substituted by 1, 2, 3, 4 or 5 independently selected from the following Group substitution: halo, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O )NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 .

In some embodiments, R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from H, halo, C _1-6 alkyl, and C _1-6 haloalkyl, wherein the The C _1-6 alkyl group is optionally substituted with 1 or 2 substituents independently selected from the following: halo, CN, NO ₂ , OR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 .

In some embodiments, R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from H, halo, C _1-6 alkyl, and C _1-6 haloalkyl, wherein the The C _1-6 alkyl group is optionally substituted ^{by OR a3.}

In some embodiments, R ¹ is H or C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted ^{with OR a3} , NR ^c3 R ^d3 and NR ^c3 C(O)R ^b3. In some embodiments, R ¹ is H or C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted ^{with OR a3.} In some embodiments, R ¹ is H or C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted with methoxy. In some embodiments, R ¹ is H or methyl; wherein the methyl group is optionally substituted with methoxy. In some embodiments, R ¹ is H, methyl, methoxymethyl, CH ₂ OH, CH(OH)CH ₃ , CH ₂ NHCH ₂ CF ₃ or CH ₂ NHC(O)CH ₃ . In some embodiments, R ¹ is H, methyl, or methoxymethyl.

In some embodiments, R ¹ is a C _1-6 alkyl group ^{optionally substituted with OR a3.} In some embodiments, R ¹ _{is a C 1-6} alkyl group optionally substituted with methoxy. In some embodiments, R ¹ is a methyl group optionally substituted with a methoxy group. In some embodiments, R ¹ is a methyl group. In some embodiments, R ¹ is methoxymethyl.

In some embodiments, R ¹ is H.

In some embodiments, R ² is H.

In some embodiments, R ⁵ is H or C _1-6 alkyl.

In some embodiments, R ⁵ is a methyl group.

In some embodiments, R ⁵ is H.

In some embodiments, R ⁶ is H.

In some embodiments, R ⁷ is H or C _1-6 alkyl.

In some embodiments, R ⁷ is CH ₂ .

In some embodiments, R ⁷ is H.

In some embodiments, R ⁸ is H.

In some embodiments, the R ^{Y groups of R 1} and Y ¹ together with the atoms to which they are attached and together with ^{the atoms forming Y 1} form a 4-10 membered heterocycloalkyl ring, which is optionally connected to 1, 2, or 3 Substitutions independently selected from the following substituents: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C (O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C( =NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O )NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 .

In some embodiments, the R ^{Y groups of R 1} and Y ¹ together with the atoms to which they are attached and together with ^{the atoms forming Y 1} form an azetidine ring, which is independently selected from 1, 2 or 3 as the case may be. Substitution from the following substituents: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O) R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 ) R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 .

In some embodiments, the R ^{Y groups of R 1} and Y ¹ together with the atoms to which they are attached and together with ^{the atoms forming Y 1} form an azetidine ring.

In some embodiments, the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are attached and together with the atoms ^{forming Y 3} and with the carbon atoms substituted ^{by R 9} , R ¹⁰ , R ¹¹ and R ^{12 (if present} ) Together to form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC (O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C (=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 .

In some embodiments, the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are attached and together with the atoms ^{forming Y 3} and with the carbon atoms substituted ^{by R 9} , R ¹⁰ , R ¹¹ and R ^{12 (if present} ) Together to form a pendant oxypyrrolidine ring or pyrrolidine ring, which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 .

In some embodiments, the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are attached and together with the atoms ^{forming Y 3} and with the carbon atoms substituted ^{by R 9} , R ¹⁰ , R ¹¹ and R ^{12 (if present} ) Together to form a pyrrolidine ring or a pendant oxypyrrolidine ring.

In some embodiments, the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are attached and together with the atoms ^{forming Y 3} and with the carbon atoms substituted ^{by R 9} , R ¹⁰ , R ¹¹ and R ^{12 (if present} ) Together to form a pendant oxypyrrolidine ring.

In some embodiments, the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are attached and together with the atoms ^{forming Y 3} and with the carbon atoms substituted ^{by R 9} , R ¹⁰ , R ¹¹ and R ^{12 (if present} ) Together to form a pendant hexahydropyridine ring.

In some embodiments, ring D is a monocyclic or polycyclic 4-10 membered heterocycloalkyl group, which is optionally substituted with 1, 2 or 3 groups independently selected from the following: halo, C _1-6 Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 , where the C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are each substituted with 1, 2 or 3 groups independently selected from the following groups as appropriate: halo, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , C(=NR ^e2 ) NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S (O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 .

In some embodiments, ring D is a monocyclic or polycyclic 4-6 membered heterocycloalkyl substituted with 1, 2, 3, or 4 substituents independently selected from the following as appropriate: halo, CN, OR ^a2 , C(O)NR ^c2 R ^d2 , C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments, ring D is a monocyclic or polycyclic 4-6 membered heterocycloalkyl group substituted with 1, 2, 3, or 4 substituents independently selected from the following: halo, OR ^a2 , C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments, Ring D is 3-azabicyclo[3.1.0]hexane.

In some embodiments, ring D is a monocyclic 4-6 membered heterocycloalkyl substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, OR ^a2 , C _{1- 6} alkyl and C _1-6 haloalkyl. In some embodiments, ring D is a polycyclic 10-membered heterocycloalkyl group substituted with 1, 2, 3, or 4 substituents independently selected from the following: halo, OR ^a2 , C _1-6 Alkyl and C _1-6 haloalkyl. In some embodiments, Ring D is an azetidine ring or a hexahydropyridine ring; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the following: halo, OR ^a2 , C _1-6 alkyl and C _1-6 haloalkyl. In some embodiments, ring D is a hexahydropyridine ring substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, OR ^a2 , C _1-6 alkyl, and C _{1 as appropriate. -6} haloalkyl. In some embodiments, ring D is a hexahydropyridine ring substituted with 1 or 2 substituents independently selected from the group consisting of OH, F, C(O)NH ₂ or CN as appropriate. In some embodiments, ring D is an azetidine ring substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, OR ^a2 , C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments, Ring D is a monocyclic 4-6 membered heterocycloalkyl. In some embodiments, Ring D is a polycyclic 10-membered heterocycloalkyl. In some embodiments, ring D is an azetidine ring or a hexahydropyridine ring. In some embodiments, ring D is a hexahydropyridine ring. In some embodiments, ring D is an azetidine ring.

In some embodiments, ring D is a monocyclic 4-6 membered heterocycloalkyl substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, OR ^a2 , C _{1- 6} alkyl and C _1-6 haloalkyl.

In some embodiments, ring D is an azetidine ring or a hexahydropyridine ring substituted ^{with OR a2 as appropriate.}

In some embodiments, ring D is a hexahydropyridine ring optionally substituted with OH.

In some embodiments, ring D is a hexahydropyridine ring.

In some embodiments, Z is Cy ^Z , halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C(O)R ^b , C(O)NR ^c R ^d , C(O)OR ^a , OC(O)R ^b , OC(O)NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c C(O)OR ^a , NR ^c C(O)NR ^c R ^d , C(=NR ^e )R ^b , C(=NR ^e )NR ^c R ^d , NR ^c C (=NR ^e )NR ^c R ^d , NR ^c S(O)R ^b , NR ^c S(O) ₂ R ^b , NR ^c S(O) ₂ NR ^c R ^d , S(O)R ^b , S( O) NR ^c R ^d , S(O) ₂ R ^b and S(O) ₂ NR ^c R ^d ; wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl groups of Z And C _1-6 haloalkyl groups are each substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: Cy ^Z , halo, CN, NO ₂ , OR ^a , SR ^a , C (O)R ^b , C(O)NR ^c R ^d , C(O)OR ^a , OC(O)R ^b , OC(O)NR ^c R ^d , C(=NR ^e )NR ^c R ^d , NR ^c C(=NR ^e )NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c C(O)OR ^a , NR ^c C(O)NR ^c R ^d , NR ^c S( O) R ^b , NR ^c S(O) ₂ R ^b , NR ^c S(O) ₂ NR ^c R ^d , S(O)R ^b , S(O)NR ^c R ^d , S(O) ₂ R ^b And S(O) ₂ NR ^c R ^d .

In some embodiments, Z is Cy ^Z , halo, C _1-6 alkyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C(O)R ^b , C(O )NR ^c R ^d , C(O)OR ^a , OC(O)R ^b , OC(O)NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c C(O)OR ^a , NR ^c C(O)NR ^c R ^d , NR ^c S(O) ₂ R ^b , NR ^c S(O) ₂ NR ^c R ^d , S(O) ₂ R ^b and S(O) ₂ NR ^c R ^d ; wherein the C _1-6 ^{alkyl group of Z is} optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: Cy Z, halo, CN, NO ₂ , OR ^a , SR ^a , C(O)R ^b , C(O)NR ^c R ^d , C(O)OR ^a , OC(O)R ^b , OC(O)NR ^c R ^d , NR ^c R ^d , NR ^c C (O)R ^b , NR ^c C(O)OR ^a , NR ^c C(O)NR ^c R ^d , NR ^c S(O) ₂ R ^b , NR ^c S(O) ₂ NR ^c R ^d , S( O) ₂ R ^b and S(O) ₂ NR ^c R ^d .

In some embodiments, Z is Cy ^Z , halo, C _1-6 alkyl, C _1-6 haloalkyl, or CN.

In some embodiments, Z is Cy ^Z.

In some embodiments, Cy ^Z _{is a 5-6 membered heteroaryl group optionally substituted with 1 , 2} , 3, or 4 substituents independently selected from the following: halo, C 1-6 alkyl, C 2 _-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O )OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S (O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 , where these alkyl groups, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, CN, NO ₂ , OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(= NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ) ₂ NR ^c1 R ^d1 .

In some embodiments, Cy ^Z is a 5 or 6-membered heteroaryl substituted with halo, CN, methyl, or C _{1-3 haloalkyl.}

In some embodiments, Cy ^Z is a 5-membered heteroaryl substituted with halo, CN, or C _{1-3 haloalkyl.} In some embodiments, Cy ^Z is a 6-membered heteroaryl substituted with halo, CN, methyl, or C _{1-3 haloalkyl.} In some embodiments, Cy ^Z is a 6-membered heteroaryl substituted with halo, CN, or C _{1-3 haloalkyl.}

In some embodiments, Cy ^Z is pyrimidinyl, pyridine, pyridyl, or thiazolyl substituted with halo, CN, or C _{1-3 haloalkyl.} In some embodiments, Cy ^Z is pyrimidinyl, pyrimidinyl, or pyridinyl substituted with halo, CN, or C _{1-3 haloalkyl.} In some embodiments, Cy ^Z is pyrimidinyl or pyrimidinyl substituted with halo, CN, or C _{1-3 haloalkyl.} In some embodiments, Cy ^Z is a pyrimidinyl substituted _{with CF 3.} In some embodiments, Cy ^Z is a thiazolyl substituted with halo, CN, or C _{1-3 haloalkyl.}

In some embodiments, Cy ^{Z is} selected from 5-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethyl)thiazol-2-yl, 5-(trifluoromethyl)pyrimidin-2 -Base, 5-(difluoromethyl)pyrimidin-2-yl, 5-(difluoromethyl)pyrimidin-2-yl, 5-fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-bromopyrimidin-2-yl, 5-cyanopyridin-2-yl, 5-cyanothiazol-2-yl, 5-cyanopyrimidin-2-yl, 5-methylpyrimidin-2-yl.

In some embodiments, Cy ^{Z is} selected from 5-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethyl)thiazol-2-yl, 5-(trifluoromethyl)pyrimidin-2 -Yl, 5-cyanopyridin-2-yl, 5-(difluoromethyl)pyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-(difluoromethyl)pyrimidin-2-yl And 5-bromopyrimidin-2-yl.

In some embodiments, Cy ^Z is 5-(trifluoromethyl)pyrimidin-2-yl.

In some embodiments, m is 1.

In some embodiments, n is zero.

In some embodiments, p is zero.

In some embodiments, q is zero.

In some embodiments, r is 1. In some embodiments, r is zero.

In some embodiments, a is zero.

In some embodiments, X is CF ₃ , Y ¹ is NR ^Y , Y ² is O, Y ³ is C(=O)NR ^Y , R ¹ is methyl, R ² is H, R ⁵ is H, R ⁶ is H, R ⁷ is CH ₂ , R ⁸ is H, ring D is hexahydropyridine substituted with OH and Z is Cy ^Z , where Cy ^Z is pyrimidinyl substituted with CF _3.

IIa， 或其醫藥上可接受之鹽。In some embodiments, provided herein are compounds of formula IIa:

IIa, or a pharmaceutically acceptable salt thereof.

IIb， 或其醫藥上可接受之鹽。In some embodiments, provided herein are compounds of Formula IIb:

IIb, or a pharmaceutically acceptable salt thereof.

IIc； 或其醫藥上可接受之鹽，其中Z¹ 及Z² 各自獨立地選自N及CH，且其中R^Z 係鹵基、CN或C_1-3 鹵烷基。在一些實施例中，R^Z 選自CF₃ 、CN、CF₂ H及Cl。In some embodiments, provided herein are compounds of formula IIc:

IIc; or a pharmaceutically acceptable salt thereof, wherein Z ¹ and Z ² are each independently selected from N and CH, and wherein R ^Z is halo, CN or C _1-3 haloalkyl. In some embodiments, R ^{Z is} selected from CF ₃ , CN, CF ₂ H, and Cl.

IId； 或其醫藥上可接受之鹽。 在一些實施例中，本發明化合物具有式IIe：

IIe； 或其醫藥上可接受之鹽。In some embodiments, the compounds of the invention have formula IId:

IId; or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the invention have formula IIe:

IIe; or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein: X is Cl, Br or CF ₃ ;

(A-1a) Y¹ 、Y² 及Y³ 各自獨立地選自O、NR^Y 、C(=O)及C(=O)NR^Y ，其中各R^Y 獨立地係H或C_1-4 烷基； Z係Cy^Z ； Cy^Z 選自5-10員雜芳基，其視情況由1、2、3或4個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、C(=NR^e1 )NR^c1 R^d1 、NR^c1 C(=NR^e1 )NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)OR^a1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 S(O)R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 及S(O)₂ NR^c1 R^d1 ，其中該等烷基、C_2-6 烯基及C_2-6 炔基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、CN、NO₂ 、OR^a1 、SR^a1 、C(O)R^b1 、C(O)NR^c1 R^d1 、C(O)OR^a1 、OC(O)R^b1 、OC(O)NR^c1 R^d1 、C(=NR^e1 )NR^c1 R^d1 、NR^c1 C(=NR^e1 )NR^c1 R^d1 、NR^c1 R^d1 、NR^c1 C(O)R^b1 、NR^c1 C(O)OR^a1 、NR^c1 C(O)NR^c1 R^d1 、NR^c1 S(O)R^b1 、NR^c1 S(O)₂ R^b1 、NR^c1 S(O)₂ NR^c1 R^d1 、S(O)R^b1 、S(O)NR^c1 R^d1 、S(O)₂ R^b1 及S(O)₂ NR^c1 R^d1 ； 環D係單環或多環4-10員雜環烷基，其視情況經1、2或3個獨立地選自以下之基團取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a2 、SR^a2 、C(O)R^b2 、C(O)NR^c2 R^d2 、C(O)OR^a2 、OC(O)R^b2 、OC(O)NR^c2 R^d2 、C(=NR^e2 )NR^c2 R^d2 、NR^c2 C(=NR^e2 )NR^c2 R^d2 、NR^c2 R^d2 、NR^c2 C(O)R^b2 、NR^c2 C(O)OR^a2 、NR^c2 C(O)NR^c2 R^d2 、NR^c2 S(O)R^b2 、NR^c2 S(O)₂ R^b2 、NR^c2 S(O)₂ NR^c2 R^d2 、S(O)R^b2 、S(O)NR^c2 R^d2 、S(O)₂ R^b2 及S(O)₂ NR^c2 R^d2 ，其中該等C_1-6 烷基、C_2-6 烯基及C_2-6 炔基各自視情況經1、2或3個獨立地選自以下之基團取代：鹵基、CN、NO₂ 、OR^a2 、SR^a2 、C(O)R^b2 、C(O)NR^c2 R^d2 、C(O)OR^a2 、OC(O)R^b2 、OC(O)NR^c2 R^d2 、C(=NR^e2 )NR^c2 R^d2 、NR^c2 C(=NR^e2 )NR^c2 R^d2 、NR^c2 R^d2 、NR^c2 C(O)R^b2 、NR^c2 C(O)OR^a2 、NR^c2 C(O)NR^c2 R^d2 、NR^c2 S(O)R^b2 、NR^c2 S(O)₂ R^b2 、NR^c2 S(O)₂ NR^c2 R^d2 、S(O)R^b2 、S(O)NR^c2 R^d2 、S(O)₂ R^b2 及S(O)₂ NR^c2 R^d2 ； R¹ 、R² 、R⁵ 、R⁶ 、R⁷ 及R⁸ 各自獨立地選自H、鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基、4-10員雜環烷基-C_1-4 烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ；其中該等R¹ 、R² 、R⁵ 、R⁶ 、R⁷ 及R⁸ 之該等C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基及4-10員雜環烷基-C_1-4 烷基各自視情況經1、2、3、4或5個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 或R¹ 及Y¹ 之R^Y 基團與其連接之原子一起及與形成Y¹ 之原子一起形成4-10員雜環烷基環，其視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 或R⁷ 及Y³ 之R^Y 基團與其連接之原子一起及與形成Y³ 之原子一起形成4-10員雜環烷基環，其視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_1-6 鹵烷基、CN、NO₂ 、OR^a3 、SR^a3 、C(O)R^b3 、C(O)NR^c3 R^d3 、C(O)OR^a3 、OC(O)R^b3 、OC(O)NR^c3 R^d3 、NR^c3 R^d3 、NR^c3 C(O)R^b3 、NR^c3 C(O)OR^a3 、NR^c3 C(O)NR^c3 R^d3 、C(=NR^e3 )R^b3 、C(=NR^e3 )NR^c3 R^d3 、NR^c3 C(=NR^e3 )NR^c3 R^d3 、NR^c3 S(O)R^b3 、NR^c3 S(O)₂ R^b3 、NR^c3 S(O)₂ NR^c3 R^d3 、S(O)R^b3 、S(O)NR^c3 R^d3 、S(O)₂ R^b3 及S(O)₂ NR^c3 R^d3 ； 各R^a 、R^b 、R^c 、R^d 、R^a1 、R^b1 、R^c1 、R^d1 、R^a2 、R^b2 、R^c2 、R^d2 、R^a3 、R^b3 、R^c3 及R^d3 獨立地選自H、C_1-6 烷基、C_1-6 鹵烷基、C_2-6 烯基、C_2-6 炔基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基及4-10員雜環烷基-C_1-4 烷基，其中該等R^a 、R^b 、R^c 、R^d 、R^a1 、R^b1 、R^c1 、R^d1 、R^a2 、R^b2 、R^c2 、R^d2 、R^a3 、R^b3 、R^c3 及R^d3 之該等C_1-6 烷基、C_2-6 烯基、C_2-6 炔基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基及4-10員雜環烷基-C_1-4 烷基視情況經1、2或3個獨立地選自以下之取代基取代：鹵基、C_1-4 烷基、C_1-4 鹵烷基、C_2-6 烯基、C_2-6 炔基、CN、OR^a7 、SR^a7 、C(O)R^b7 、C(O)NR^c7 R^d7 、C(O)OR^a7 、OC(O)R^b7 、OC(O)NR^c7 R^d7 、NR^c7 R^d7 、NR^c7 C(O)R^b7 、NR^c7 C(O)NR^c7 R^d7 、NR^c7 C(O)OR^a7 、C(=NR^e7 )NR^c7 R^d7 、NR^c7 C(=NR^e7 )NR^c3 R^d7 、S(O)R^b7 、S(O)NR^c7 R^d7 、S(O)₂ R^b7 、NR^c7 S(O)₂ R^b7 、NR^c7 S(O)₂ NR^c7 R^d7 及S(O)₂ NR^c7 R^d7 ； R^a7 、R^b7 、R^c7 及R^d7 獨立地選自H、C_1-6 烷基、C_1-6 鹵烷基、C_2-6 烯基、C_2-6 炔基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基及4-10員雜環烷基-C_1-4 烷基，其中該等C_1-6 烷基、C_1-6 鹵烷基、C_2-6 烯基、C_2-6 炔基、C_6-10 芳基、C_3-7 環烷基、5-10員雜芳基、4-10員雜環烷基、C_6-10 芳基-C_1-4 烷基、C_3-7 環烷基-C_1-4 烷基、5-10員雜芳基-C_1-4 烷基及4-10員雜環烷基-C_1-4 烷基各自視情況經1、2或3個獨立地選自以下之取代基取代：OH、CN、胺基、鹵基、C_1-6 烷基、C_1-6 烷氧基、C_1-6 鹵烷基及C_1-6 鹵烷氧基；且 各R^e 、R^e1 、R^e2 、R^e3 及R^e7 獨立地選自H、C_1-4 烷基及CN； 其中任何上文所提及之雜芳基或雜環烷基包含1、2、3或4個獨立地選自O、N及S之成環雜原子；且 其中任何上文所提及之雜環烷基之一或多個成環C或N原子視情況由1或2個側氧基(=O)基團取代。A is a group having the formula (A-1a):

(A-1a) Y ¹ , Y ² and Y ³ are each independently selected from O, NR ^Y , C(=O) and C(=O)NR ^Y , wherein each R ^{Y is} independently H or C _1-4 Alkyl; Z is Cy ^Z ; Cy ^{Z is} selected from 5-10 membered heteroaryl groups, which are optionally substituted by 1, 2, 3, or 4 substituents independently selected from the following: halo, C _1-6 alkane Group, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 , among which Alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, CN, NO ₂ , OR ^a1 , SR ^a1 , C (O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S( O) R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 And S(O) ₂ NR ^c1 R ^d1 ; Ring D is a monocyclic or polycyclic 4-10 membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from the following: halo , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C( O)NR ^c2 R ^d2 、C(O)OR ^a2 、OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S (O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 , wherein these C _1-6 alkyl, C _2-6 alkenyl and Each C _2-6 alkynyl group is optionally substituted with 1, 2 or 3 groups independently selected from the following: halo, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O )NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S( O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _{1- 4-} alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl, 4-10 membered heterocycloalkyl-C _1-4 alkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; among these R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ The C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 members Heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl- Each of C _1-4 alkyl and 4-10 membered heterocycloalkyl-C _1-4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O) NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O ) R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or the R ^{Y groups of R 1} and Y ¹ together with the atoms to which they are connected and together with ^{the atoms forming Y 1} form a 4-10 membered heterocycloalkyl ring, which is subject to 1 , 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO _2. OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O ) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ⁷ and Y ³ of R ^Y The group and the atom to which it is attached and together with the atom forming Y ³ form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O) NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O ) R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; each R ^a , R ^b , R ^c , ^Rd , R ^a1 , R ^b1 , R ^c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 , R ^d2 , R ^a3 , R ^b3 , R ^c3 and R ^{d3 are} independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _{1- 4} alkyl, 5-10 membered heteroaryl, -C _1-4 alkyl, and 4-10 membered heterocycloalkyl -C _1-4 alkyl, wherein these ^{R a, R b, R c} , R d, R ^a1 , R ^b1 , R ^c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 , R ^d2 , R ^a3 , R ^b3 , R ^c3 and R ^d3 such C _1-6 alkyl, C _2-6 alkene Group, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered hetero Aryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl and 4-10 membered heterocycloalkyl-C _1-4 alkyl are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O)NR ^c7 R ^d7 , C(O) OR ^a7 , OC(O)R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)NR ^c7 R ^d7 , NR ^c7 C(O) OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; R ^a7 , R ^b7 , R ^c7 and R ^{d7 are} independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl Group, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _{1 -4} alkyl and 4-10 membered heterocycloalkyl-C _1-4 alkyl, wherein these C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl, and 4-10 membered heterocycloalkyl-C _1-4 alkyl are each subject to 1, 2 or 3 substituents independently selected from the following: OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, and C _{1- 6} haloalkoxy; and each of R ^e , R ^e1 , R ^e2 , R ^e3 and R ^{e7 is} independently selected from H, C _1-4 alkyl and CN; wherein any of the above-mentioned heteroaryl or hetero The cycloalkyl group contains 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N and S; and any one or more of the above-mentioned heterocycloalkyl groups form a ring C or N The atom is optionally substituted with 1 or 2 pendant oxy (=O) groups.

In some embodiments, provided herein is a compound selected from the group consisting of: (S)-2-(2-(6-Pendoxy-5-(trifluoromethyl)-1,6-dihydrogen-4- (Amino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide; (S)-N-methyl- 2-(2-(6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-ylamino)propoxy)-N-(1-(5-( Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide; (S)-N-methyl-2-(2-((6-oxo-5-(trifluoro (Methyl)-1,6-Dihydrotetrakis-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)thiazol-2-yl)hexahydropyridine-4 -Yl) acetamide; (S)-N-methyl-2-(2-(6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrotetrakis-4-ylamine Yl)propoxy)-N-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)acetamide; ((S)-N-methyl- 2-(2-(6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-ylamino)propoxy)-N-(1-(5-( (Trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)acetamide; (S)-N-(1-(5-cyanopyridin-2-yl)hexahydropyridine-4- Yl)-N-methyl-2-(2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)amino)propoxy) Acetamide; (S)-N-Ethyl-2-(2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)amino )Propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide; (S)-N-methyl-2-( (1-(6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotetrakis-4-yl)azetidin-2-yl)methoxy)-N-(1 -(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide; (S)-2-(3-methoxy-2-((6-oxo -5-(trifluoromethyl)-1,6-dihydrotetra-4-yl)amino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl) Pyrimidine-2-yl)hexahydropyridin-4-yl)acetamide; 5-(( S )-1-(( S )-1-(1-(5-(trifluoromethyl)pyrimidine-2- Yl)hexahydropyridin-4-yl)-2-side oxypyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pyridine-3(2 H ) -Ketone; 5-(( S )-1-(( R )-1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxo Pyrrolidin-3-yloxy)prop-2-ylamino)-4-(trifluoromethyl)pyridine-3(2 H )-one; 4-chloro-5-((S )-1-(2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yloxy)propan- 2-ylamino)da 𠯤-3(2H)-one; 4-bromo-5-(((2S)-1-((2-side oxy-1-(1-(5-(trifluoromethyl) (Pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)pyridine-3(2H)-one; 5-(( (S)-1-(((S)-2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidine- 3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-(((R) -2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2- Yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 6-(4-((R)-2-oxo-3-((S)-2-( (6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl ) Nicotine carbonitrile; 6-(4-((S)-2-Pendant oxy-3-((S)-2-((6-Pendent oxy-5-(trifluoromethyl)-1, 6-Dihydropyridine-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-(( (S)-1-(1-(5-(Difluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop- 2-yl)amino)-4-(trifluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((R)-1-(1-(5- (Difluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(tri Fluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)hexahydropyridine-4) -Yl)-2-pendant oxypyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 6-( 4-((S)-3-((S)-3-Methoxy-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4- Yl)amino)propoxy)-2-side oxypyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-(4-((R)-3-((S )-3-Methoxy-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy)-2- Pendant pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-methoxy-3-(((S)-2-pendant oxy) -1-(1 -(5-(Trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoro Methyl) 𠯤-3(2H)-one; (S)-N-methyl-2-(2-(6-oxo-5-(trifluoromethyl)-1,6-dihydro 𠯤-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)acetamide; 5-(( (S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4- (Yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridine-3(2H)-one; 5-(((S)-1- Methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine-3 -Yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((S)- 2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl) Oxy)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-(((R)-2-side oxy-1-(1-( 5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl) Da 𠯤-3(2H)-one; 4-(trifluoromethyl)-5-(((2S)-1-((1-(1-(5-(trifluoromethyl)pyrimidin-2-yl )Hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)pyridine-3(2H)-one; 5-(((S)-1-(( (S)-1-(1-(5-(Difluoromethyl)pyrrolidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propane -2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-(((R)-1-(1-(5 -(Difluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)amino)-4- (Trifluoromethyl) 𠯤-3(2H)-one; 4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5- (Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)Pyridox-3(2H)-one; 5 -(((S)-1-(((R)-1-(1-(5-Bromopyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl )Oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridine-3(2H)-one; (S)-N-methyl-2-(2-((6- Pendant oxy-5-(trifluoromethyl)-1,6-dihydrod-4-yl)oxy)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidine- 2-yl)hexahydropyridin-4-yl)acetamide; 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl) (Yl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pyridine-3(2H )-Ketone; 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pyridine-3(2H)-one; 5-(((R)- 1-(((S)-2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)amine Yl)propan-2-yl)amino)-4-(trifluoromethyl)pyridine-3(2H)-one; 5-(((R)-1-(((R)-2-oxo Base-1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)amino)prop-2-yl)amino)- 4-(Trifluoromethyl) 𠯤-3(2H)-one; 5-(((2S)-1-((1-(1-(5-(Difluoromethyl)pyrimidin-2-yl) Hexahydropyridin-4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl) 𠯤-3(2H)- Ketone; (S)-2-(2-((5-bromo-6-pendant oxy-1,6-dihydrothia-4-yl)oxy)propoxy)-N-methyl-N -(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide; 5-(((2S)-1-(methyl(2-oxo -1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)amino)prop-2-yl)amino)-4 -(Trifluoromethyl) 𠯤-3(2H)-one; 6-(4-(2-side oxy-3-((S)-2-((6-side oxy-5-(tri Fluoromethyl)-1,6-Dihydrotetrakis-4-yl)oxy)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-((( S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidine-3 -Yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((R)- 2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl ) Oxy)-4-(trifluoromethyl) 𠯤-3(2H)-one; 4-bromo-5-(((S)-1-(((R)-2-oxo-1 - (1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino) 𠯤-3( 2H)-ketone; N-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-((S) -2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotap-4-yl)amino)propoxy)acetamide; and N-((3S ,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-((S)-2-((6-side oxy -5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy)acetamide; or pharmaceutically acceptable of any of the above Salt.

In some embodiments, provided herein is a compound selected from: (S)-3-((S)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy) -1'-(5-(trifluoromethyl)pyrimidin-2-yl)-[1,4'-bihexahydropyridine]-2-one; (R)-3-((S)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy) -1'-(5-(trifluoromethyl)pyrimidin-2-yl)-[1,4'-bihexahydropyridine]-2-one; 5-(((S)-1-(((S)-4,4-dimethyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl) Hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; 5-(((S)-1-(((R)-4,4-dimethyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl) Hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; (R)-6-(4-(2-Pendant oxy-3-(2-((6-Pendent oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4-yl ) Amino) ethoxy) pyrrolidin-1-yl) hexahydropyridin-1-yl) nicotine carbonitrile; (S)-6-(4-(2-Pendant oxy-3-(2-((6-Pendent oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl ) Amino) ethoxy) pyrrolidin-1-yl) hexahydropyridin-1-yl) nicotine carbonitrile; 5-(((S)-1-(((3S,4R)-4-methyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa (Hydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; 5-(((S)-1-(((3R,4S)-4-methyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa (Hydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; 5-(((S)-1-(((R)-1-((3R,4R)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3S,4S)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3S,4R)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3R,4S)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 6-((R)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl) )-1,6-dihydropyridine-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-((S)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl) )-1,6-dihydropyridine-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-(((R)-1-(1-(5-chloropyridine-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -(Yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; 5-(((S)-1-(((R)-1-(1-(5-fluoropyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3- (Yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-(((R)-2-side oxy-1-((1R,5S,6s)-3-(5-(trifluoromethyl)pyrimidin-2-yl) -3-Azabicyclo[3.1.0]hex-6-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)da𠯤-3 (2H)-ketone; 5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -(Yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; 5-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro) -4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)pyridine-2-carbonitrile; 4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridine) -4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 4-bromo-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridine) -4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 4-chloro-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 4-chloro-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 6-(4-((R)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrota𠯤-4-yl)oxy)propoxy )-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-(4-((S)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrota𠯤-4-yl)oxy)propoxy )-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-(((S)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -Yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -Yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl) 𠯤-3(2H)-one; 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydrota𠯤 -4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydrota𠯤 -4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro (Pyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)dash-3(2H)-one; 5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro (Pyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)dash-3(2H)-one; 5-(((S)-1-methoxy-3-(((S)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-side (Oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-methoxy-3-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-side (Oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-methoxy-3-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-side (Oxypyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 2-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydrota𠯤 -4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)thiazole-5-carbonitrile; 6-(4-((S)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrota 𠯤-4-yl)oxy)-3- (Methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-(4-((R)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrotap-4-yl)oxy)-3- (Methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 4-Bromo-5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine-2- (Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 4-Bromo-5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine-2- (Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 5-(((S)-1-(((R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; (S)-N-((R)-2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine-3- Yl)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotap-4-yl)amino)propanamide; 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl) (Pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pada𠯤- 3(2H)-ketone; 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-(((S)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((2S)-1-((1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)taka-3(2H)-one; N-((S)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrole (Pyridin-3-yl)oxy)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propyl)acetate amine; 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro (Pyridin-4-yl)pyrrolidin-3-yl)oxy)but-2-yl)amino)-4-(trifluoromethyl)dash-3(2H)-one; 4-((R)-2-Pendant oxy-3-((S)-2-((6-Pendent oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4- (Yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carboxamide; and 4-((R)-2-Pendant oxy-3-((S)-2-((6-Pendent oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4- (Yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carbonitrile; Or a pharmaceutically acceptable salt of any of the above.

It should be further understood that certain features of the invention set forth in the context of separate embodiments for clarity can also be provided in combination in a single embodiment. Conversely, the various features of the invention set forth in the context of a single embodiment for clarity can also be provided individually or in any suitable subcombination.

In each position in this specification, the substituents of the compounds of the present invention are disclosed in groups or ranges. The present invention is expressly intended to include each and each individual sub-combination of members of these groups and ranges. For example, the term "C _1-6 alkyl" is intended to expressly disclosed individually methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

In each position in this specification, various aryl, heteroaryl, cycloalkyl and heterocycloalkyl rings are described. Unless otherwise specified, the rings may be attached to the rest of the molecule at any ring member permitted by the valence. For example, the terms "pyridinyl", "pyridyl" or "pyridyl ring" can refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

The term "n-member" (where "n" is an integer) usually states that the number of ring atoms is the number of ring atoms in the portion of "n". For example, hexahydropyridyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1, 2,3,4-Tetrahydro-naphthalene is an example of 10-membered cycloalkyl.

For compounds of the invention in which a variable occurs more than once, each variable can be a different part independently selected from the group defining the variable. For example, if a structure with two R groups simultaneously present on the same compound is described, the two R groups can represent different parts independently selected from the groups defined for R.

As used herein, the phrase "substituted as appropriate" means unsubstituted or substituted.

The term "substituted" as used herein means the replacement of a hydrogen atom by a non-hydrogen group. It should be understood that substitution at a given atom is limited by valence.

As used herein, the term "C _ij "(where i and j are integers) used in combination with a chemical group designates the range of the number of carbon atoms in the chemical group, where ij defines the range. For example, C _1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

As used herein, the term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group that can be straight or branched. In some embodiments, the alkyl group contains 1 to 7, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, tertiary butyl, n-pentyl Group, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl and the like. In some embodiments, the alkyl group is methyl, ethyl, or propyl.

As used herein, "halo" or "halogen" used alone or in combination with other terms includes fluorine, chlorine, bromine, and iodine. In some embodiments, the halo group is F or Cl.

As used herein, the term "haloalkyl" used alone or in combination with other terms refers to an alkyl group having halogen atom substituents with at most full valences, and these halogen atom substituents may be the same or different. In some embodiments, the halogen atom is a fluorine atom. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF ₃ , C ₂ F ₅ , CHF ₂ , CCl ₃ , CHCl ₂ , C ₂ Cl ₅ and the like.

As used herein, the term "alkoxy" used alone or in combination with other terms refers to a group of formula -O-alkyl. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, "haloalkoxy" used alone or in combination with other terms refers to a group of formula -O-(haloalkyl). In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An exemplary haloalkoxy group is -OCF ₃ .

As used herein, "amino" used alone or in combination with other terms refers to NH ₂ .

As used herein, the term "alkylamino" used alone or in combination with other terms refers to a group of formula -NH (alkyl). In some embodiments, the alkylamino group has 1 to 6 or 1 to 4 carbon atoms. Exemplary alkylamino groups include methylamino, ethylamino, propylamino (eg, n-propylamino and isopropylamino), and the like.

As used herein, the term "dialkylamino" used alone or in combination with other terms refers to a group of formula -N(alkyl) ₂ . Exemplary dialkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), and the like. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term "heterocycloalkyl", used alone or in combination with other terms, refers to a non-aromatic ring or ring system, which optionally contains one or more alkenylene or alkynylene groups as part of the ring structure, The ring structure has at least one heteroatom ring member independently selected from nitrogen, sulfur, oxygen, and phosphorus. Heterocycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, the heterocycloalkyl group has 1, 2, 3, or 4 monocyclic or bicyclic groups independently selected from nitrogen, sulfur, and oxygen heteroatoms. The definition of heterocycloalkyl also includes those having one or more aromatic rings (for example, aryl or heteroaryl ring) fused with a non-aromatic heterocycloalkyl ring (that is, having a bond in common with it) Part, for example, 1,2,3,4-tetrahydro-quinoline and the like. Heterocycloalkyl groups may also include bridgehead heterocycloalkyl groups (e.g., heterocycloalkyl moieties containing at least one bridgehead atom, such as azaadamantan-1-yl and the like) and spiroheterocycloalkyl groups (e.g., containing at least The heterocycloalkyl moiety of two rings fused at a single atom, for example [1,4-dioxa-8-aza-spiro[4.5]dec-N-yl] and the like). In some embodiments, the heterocycloalkyl group has 3 to 10 ring-forming atoms, 4 to 10 ring-forming atoms, or about 3 to 8 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, the heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. The carbon atoms or heteroatoms in the heterocycloalkyl ring can be oxidized to form a carbonyl group, N-oxide or sulfonyl group (or other oxidative linkage), or the nitrogen atom can be quaternary ammonium. In some embodiments, the heterocycloalkyl moiety is a C _2-7 monocyclic heterocycloalkyl. In some embodiments, the heterocycloalkyl group is a morpholine ring, pyrrolidine ring, hexahydropyridine ring, hexahydropyridine ring, tetrahydropyran ring, tetrahydropyridine, azetidine ring, or tetrahydrofuran ring.

As used herein, the term "heterocycloalkyl", used alone or in combination with other terms, refers to a group of the formula heterocycloalkyl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is methylene. In some embodiments, the heterocycloalkyl moiety has 3 to 10 ring members, 4 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl moiety is a monocyclic ring. In some embodiments, the heterocycloalkyl moiety is a C _2-7 monocyclic heterocycloalkyl.

As used herein, the term "aryl" used alone or in combination with other terms refers to a monocyclic or polycyclic (eg fused ring system) aromatic hydrocarbon moiety, such as but not limited to phenyl, 1-naphthyl, 2-naphthalene Base and so on. In some embodiments, the aryl group has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the aryl group is phenyl or naphthyl.

As used herein, the term "arylalkyl" used alone or in combination with other terms refers to a group of the formula aryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is methylene. In some embodiments, the aryl moiety is phenyl. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, arylalkyl is benzyl.

As used herein, the term "heteroaryl", used alone or in combination with other terms, refers to a monocyclic or polycyclic ring having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen (e.g., fused ring system ) Aromatic hydrocarbon part. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Exemplary heteroaryl groups include (but are not limited to) pyridyl, pyrimidinyl, pyrrolyl, pyridyl, trisyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazole Group, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, iso Thiazolyl, purinyl, carbazolyl, benzimidazolyl, indoline, pyrrolyl, oxazolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2- b] Thiazolyl or the like. The carbon atoms or heteroatoms in the heteroaryl ring can be oxidized to form a carbonyl group, N-oxide or sulfonyl group (or other oxidative bonds), or the nitrogen atom can be quaternary ammonium, and the condition is to preserve the ring Aromatic properties. In some embodiments, the heteroaryl group has 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

As used herein, the term "heteroarylalkyl" used alone or in combination with other terms refers to a group of the formula heteroaryl-alkyl-. In some embodiments, the alkyl moiety has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atom. In some embodiments, the alkyl moiety is methylene. In some embodiments, the heteroaryl moiety is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl moiety has 5 to 10 carbon atoms.

The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise stated, all stereoisomers (e.g., enantiomers and diastereomers) are expected. The compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic form. Methods of how to prepare optically active forms from optically inactive starting materials are known in the art, for example, by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, and the like may also be present in the compounds described herein, and all such stable isomers are considered in the present invention. The cis and trans geometric isomers of the compounds of the present invention can be separated as a mixture of isomers or as separate isomers.

。 本發明化合物亦包括中間體或最終化合物中出現之原子之所有同位素。同位素包括具有相同原子數但不同質量數之彼等原子。舉例而言，氫之同位素包括氚及氘。在一些實施例中，本發明化合物包括至少一個氘原子。Huaweiheng of the present invention also includes tautomeric forms. The tautomeric form results from the exchange of single bonds with adjacent double bonds and the accompanying migration of protons. Tautomer forms include proton transfer tautomers that are isomeric protonated states with the same empirical formula and total charge. Exemplary proton transfer tautomers include keto-enol pairs, amide-imidic acid pairs, lactamine-endimines pairs, enamine-imine pairs, and protons can occupy two of the heterocyclic ring systems. Ring form of one or more positions, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H- Pyrazole. Tautomeric forms can be in equilibrium or locked in space as one form due to appropriate substitution. Examples of tautomeric forms are shown below: 𠯤-3( 2H )-ketone and 𠯤-3-ol:

. The compounds of the present invention also include all isotopes of atoms present in the intermediate or final compound. Isotopes include those atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the invention include at least one deuterium atom.

Unless otherwise specified, the term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure.

All compounds and their pharmaceutically acceptable salts can be found together with other substances (e.g. water and solvents) (e.g. in the form of hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation may include, for example, a composition enriched in a compound of the invention. Substantial separation may include at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight. % By weight of the composition of the compound of the present invention or its salt. The method of separating compounds and their salts is common in the industry.

The phrase “pharmaceutically acceptable” used in this article refers to the term “pharmaceutically acceptable” that is suitable for use in contact with human and animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and with reasonable benefits/ These compounds, materials, compositions and/or dosage forms with a risk ratio commensurate.

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by partially converting an existing acid or base into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines); basic or organic salts of acidic residues (such as carboxylic acids); and the like. The pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, the salts can be prepared by reacting the free acid or base form of the compounds with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two. A list of suitable salts can be found in Remington's Pharmaceutical Sciences , 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). All contents are incorporated into this article by reference.

Synthesis The compounds of the present invention (including their salts) can be prepared using known organic synthesis techniques, and can be synthesized according to any of many possible synthetic routes.

The reaction for preparing the compound of the present invention can be carried out in a suitable solvent that can be easily selected by a person familiar with organic synthesis technology. A suitable solvent may be substantially non-reactive with the starting material (reactant), intermediate or product at the temperature at which the reaction is carried out (for example, a temperature within the range of the solidification temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, those skilled in the art can choose a solvent suitable for the specific reaction step.

The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. Those familiar with this technology can easily determine the need for protection and deprotection and the choice of appropriate protecting groups. The chemistry of protecting groups can be found in, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety middle.

The reaction can be monitored according to any suitable method known in the industry. For example, it can be performed by spectroscopic methods (such as nuclear magnetic resonance spectroscopy (for example, ¹ H or ¹³ C), infrared spectroscopy, spectrophotometry (for example, UV-visible light) or mass spectrometry) or by chromatography (for example, high-performance liquid phase Chromatography (HPLC) or thin layer chromatography (TLC)) monitor product formation.

As used herein, the expressions "ambient temperature" and "room temperature" and "RT" are understood in the industry and generally refer to the temperature (such as the reaction temperature) of the chamber where the reaction is performed, for example, about 20°C to about 30°C temperature.

The compound of formula I can be prepared according to many preparation routes known in the literature. Exemplary synthetic methods for preparing the compounds of the present invention are provided in the following schemes. Unless otherwise stated, all substituents are as defined herein.

In the method shown in Scheme 1, the appropriately substituted halogen-containing of formula (1-1) is treated with p-methoxybenzyl chloride ("PMB-Cl") in the presence of sodium hydride (NaH) The compound (ie, X ^a = Cl or Br) is protected as a p-methoxybenzyl ether ("PMB") compound of formula (1-2).

如方案2-4中所示，在PMB保護基團去保護後，式(1-2)之化合物可與各種親核劑反應以提供式(I)化合物。 Scheme 1

As shown in Scheme 2-4, after the PMB protecting group is deprotected, the compound of formula (1-2) can react with various nucleophiles to provide the compound of formula (I).

In the method shown in Scheme 2, the compound of formula (1-3) (wherein Y ^a is O, NR ^Y or S) and the compound of formula (1-2) in a base (such as triethylamine, Cs ₂ CO ₃ or potassium tert-butoxide) to provide a compound of formula (1-4). Deprotection with acid (e.g. trifluoroacetic acid or trifluoromethanesulfonic acid in hydrochloric acid) provides compounds of formula (IA).

Scheme 2

Method of Use The compound of the present invention can inhibit the activity of PARP7. For example, by administering an inhibitory amount of the compound of the present invention to cells, individuals or patients, the compounds of the present invention can be used to inhibit the activity of PARP7 in cells or individuals or patients that need to inhibit enzymes.

As PARP7 inhibitors, the compounds of the present invention can be used to treat various diseases related to the abnormal expression or activity of PARP7. For example, the compounds of the invention can be used to treat cancer. In some embodiments, cancers that can be treated according to the present invention include breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, head and neck cancer (Upper gastrointestinal) cancer, urinary tract cancer, colon and other cancers.

In some embodiments, cancers treatable according to the present invention include hematopoietic malignancies such as leukemia and lymphoma. Example lymphomas include Hodgkin's or non-Hodgkin's lymphoma, multiple myeloma, B-cell lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)), chronic lymphocytic lymphoma ( CLL), T cell lymphoma, hair cell lymphoma and Burkett’s lymphoma. Example leukemias include acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).

Other cancers that can be treated by administering the compounds of the present invention include liver cancer (e.g., hepatocellular carcinoma), bladder cancer, bone cancer, glioma, breast cancer, cervical cancer, colon cancer, endometrial cancer, epithelial cancer, esophageal cancer , Ewing's sarcoma (Ewing's sarcoma), pancreatic cancer, gallbladder cancer, stomach cancer, gastrointestinal tumors, head and neck cancer (upper gastrointestinal cancer), bowel cancer, Kaposi's sarcoma (Kaposi's sarcoma), kidney cancer, laryngeal cancer , Liver cancer (such as hepatocellular carcinoma), lung cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer and uterine cancer.

In some embodiments, the cancers that can be treated by administering the compounds of the present invention are multiple myeloma, DLBCL, hepatocellular carcinoma, bladder cancer, esophageal cancer, head and neck cancer (upper gastrointestinal cancer), kidney cancer, prostate cancer , Rectal cancer, stomach cancer, thyroid cancer, uterine cancer and breast cancer.

The PARP7 inhibitor of the present invention may also have therapeutic use in PARP7-related disorders in the field of diseases (such as cardiology, virology, neurodegeneration, inflammation, and pain), in particular, when the disease is characterized by PARP7 overexpression or activity In the case of increase.

The term "cell" as used herein means a cell in vitro, in vitro or in vivo. In some embodiments, the ex vivo cell may be a tissue sample excised from an organism (e.g., a mammal). In some embodiments, the cells in vitro may be cells in cell culture. In some embodiments, the in vivo cell line is a cell that survives in an organism (e.g., a mammal).

The term "contact" as used herein refers to bringing together the indicated parts of an in vitro system or an in vivo system. For example, "contacting" PARP7 with the compound of the present invention or "contacting" cells with the compound of the present invention includes administering the compound of the present invention to an individual or patient (such as a human) with PARP7, and for example, introducing the compound of the present invention into a compound containing PARP7 cells or purified preparation samples.

As used herein, the terms "individual" or "patient" are used interchangeably and refer to mammals, and specifically humans.

The phrase "therapeutically effective amount" as used herein refers to the amount of an active compound or pharmaceutical agent that triggers a biological or medical response in a tissue, system, animal, individual, or human sought by researchers, veterinarians, physicians, or other clinicians.

The term "treating or treatment" as used herein refers to 1) inhibiting the disease of an individual who is experiencing or exhibiting the pathology or symptomology of the disease (ie stopping the further development of pathology and/or symptomology), or 2) To improve the disease of an individual who is experiencing or exhibiting the pathology or symptomology of the disease (ie, reversing the pathology and/or symptomology).

The term "preventing or prevention" as used herein refers to the prevention of diseases in individuals who may be susceptible to disease but have not yet experienced or exhibited the pathology or symptomology of the disease.

Combination therapy One or more additional pharmaceutical agents or treatment methods (e.g. chemotherapeutic agents or other anti-cancer agents, immunopotentiators, immunosuppressive agents, immunotherapy, radiation, anti-tumor and anti-viral vaccines, cytokine therapy (e.g. IL2, GM-CSF, etc.) and/or kinases (tyrosine or serine/threonine), epigenetic or signal transduction inhibitors) can be used in combination with the compounds of the present invention. The agents can be combined with the compounds of the present invention in a single dosage form, or the agents can be administered as separate dosage forms simultaneously or sequentially.

Agents suitable for use in combination with the compounds of the present invention for the treatment of cancer include chemotherapeutics, targeted cancer therapy, immunotherapy or radiation therapy. The compound of the present invention can be effectively used in the treatment of breast cancer and other tumors in combination with antihormonal agents. Suitable examples are anti-estrogens, including (but not limited to) tamoxifen and toremifene; aromatase inhibitors, including (but not limited to) letrozole, anastrozole Anastrozole and exemestane; adrenal corticosteroids (such as prednisone); progestins (such as megastrol acetate) and estrogen receptor antagonists (such as Fulvestrant (fulvestrant). Suitable antihormonal agents for the treatment of prostate cancer and other cancers can also be combined with the compounds of the present invention. Such antihormones include antiandrogens, including (but not limited to) flutamide, bicalutamide and nilutamide; luteinizing hormone releasing hormone (LHRH) analogs , Including leuprolide, goserelin, triptorelin, and histrelin; LHRH antagonists (such as degarelix); androgen receptor blockade Discontinuing agents (such as enzalutamide) and agents that inhibit androgen production (such as abiraterone).

Angiogenesis inhibitors can be effective in combination with FGFR inhibitors in some tumors. Such angiogenesis inhibitors include antibodies against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. VEGFR kinase inhibitors and other anti-angiogenesis inhibitors include (but are not limited to) sunitinib, sorafenib, axitinib, cediranib, Pazopanib, regorafenib, brivanib and vandetanib.

Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (including but not limited to nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas and triazynes), such as urine Pyrimidine mustard, chlormethine, cyclophosphamide (Cytoxan ^TM ), ifosfamide, melphalan, chlorambucil, piperobromide Pipobroman, triethylene-melamine, triacetylene thiophosphoramine, busulfan, carmustine, lomustine, streptozocin, Dacarbazine and temozolomide.

Other anticancer agents include antibody therapeutics directed against checkpoints or costimulatory molecules (e.g. CTLA-4, PD-1, PD-L1 or 4-1BB) or directed against cytokines (IL-10, TGF-β, etc.) The antibody. Exemplary cancer immunotherapy antibodies include pembrolizumab, ipilimumab, nivolumab, atezolizumab, and durvalumab. Additional anticancer agents include antibody therapeutics against surface molecules of blood cancers, such as ofatumumab, rituximab, and alemtuzumab.

Most of the methods for safe and effective administration of these chemotherapeutic agents are known to those familiar with the art. In addition, its investment is described in the standard literature. For example, the administration of many chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, for example, 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated by reference as described in its full text In this article.

Pharmaceutical formulations and dosage forms When used as medicines, the compounds of the present invention can be administered in the form of pharmaceutical compositions. A pharmaceutical composition refers to a combination of the compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a well-known manner in medical technology, and can be administered by various methods depending on the desired local or systemic treatment and the area to be treated. Administration can be oral, topical (including ophthalmic administration and mucosal administration, including intranasal, transvaginal and transrectal delivery), transpulmonary (for example, by inhalation or insufflation of powder or aerosol, including by mist Vasculature; intratracheal, intranasal, transepidermal and transdermal), ocular or parenteral.

The present invention also includes pharmaceutical compositions containing as active ingredients one or more of the above compounds of the present invention in combination with one or more pharmaceutically acceptable carriers. In preparing the composition of the present invention, the active ingredient is usually mixed with excipients, diluted by the excipients or encapsulated in such a carrier in the form of, for example, capsules, sachets, paper or other containers. When the excipient is used as a diluent, it can be a solid, semi-solid or liquid material, which serves as a vehicle, carrier or medium for the active ingredient. Therefore, these compositions can be in the form of tablets, pills, powders, lozenges, sachets, pills, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments ( Containing, for example, up to 10% by weight of active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

The composition can be formulated into a unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human individuals and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect and suitable pharmaceutical excipients.

The active compound is effective over a wide dosage range and is usually administered in a pharmaceutically effective amount. However, it should be understood that the actual dosage of the compound will usually be determined by the physician based on relevant conditions including the following: the condition to be treated, the route of administration selected, the actual compound to be administered, the age, weight and response of the individual patient, and the patient’s symptoms. Severity and so on.

To prepare solid compositions such as lozenges, the main active ingredients are mixed with pharmaceutical excipients to form a solid pre-formulated composition containing a homogeneous mixture of the compound of the present invention. When it is mentioned that these pre-formulated compositions are homogeneous, the active ingredients are usually uniformly dispersed throughout the composition, so that the composition can be easily subdivided into effective unit dosage forms such as tablets, pills, and capsules. This solid pre-formulated composition is then subdivided into unit dosage forms of the aforementioned type, which contain, for example, 0.1 mg to about 500 mg of the active ingredient of the present invention.

The tablets or pills of the present invention can be coated or compounded to provide a dosage form with the advantage of long-lasting action. For example, a lozenge or pill may include an internal dosage component and an external dosage component, the latter being the former in the form of a film. The two components can be separated by an enteric layer, which is used to resist decomposition in the stomach and allow the internal components to enter the duodenum intact or to delay release. A variety of materials can be used for the enteric layers or coatings, and these materials include a large number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

The compounds and compositions of the present invention can be incorporated for oral administration or by injection. Liquid forms include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions and the use of edible oils (such as cottonseed oil, sesame oil, coconut oil or Peanut oil) flavored emulsions and elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions and powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. These liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered via oral or nasal respiratory routes to obtain local or systemic effects. The composition can be atomized by using an inert gas. The nebulized solution can be directly inhaled from the nebulizing device or the nebulizing device can be attached to a mask or intermittent positive pressure breathing machine. The solution, suspension or powder composition can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

The amount of the compound or composition administered to the patient will vary depending on the drug administered, the purpose of administration (for example, prevention or treatment), the state of the patient, the mode of administration, and the like. In therapeutic applications, the composition can be administered to patients who are already suffering from the disease in an amount sufficient to cure or at least partially prevent the symptoms of the disease and its complications. The effective dose will depend on the condition of the disease to be treated and the judgment of the attending clinician based on factors such as the severity of the disease, the age, weight and overall condition of the patient, and the like.

The composition administered to the patient may be in the form of the above-mentioned pharmaceutical composition. These compositions can be sterilized by conventional sterilization techniques, or can be sterile filtered. The aqueous solution can be packaged for use as is or lyophilized, and the lyophilized formulation can be combined with a sterile aqueous vehicle before administration.

The therapeutic dose of the compound of the present invention can be changed according to, for example, the following: the specific use for the treatment, the way of administering the compound, the health and physical condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compound of the present invention in the pharmaceutical composition can vary depending on many factors, including dosage, chemical characteristics (such as hydrophobicity), and route of administration. For example, the compound of the present invention may be provided in the form of an aqueous physiological buffer solution containing about 0.1% w/v to about 10% w/v for parenteral administration of the compound. Some typical dosage ranges are about 1 µg/kg to about 1 g/kg body weight/day. In some embodiments, the dosage range is about 0.01 mg/kg to about 100 mg/kg body weight/day. The dosage may depend on variables such as the type and degree of progression of the disease or disorder, the overall health status of a particular patient, the relative biological potency of the selected compound, the formulation of excipients and the route of administration, etc. The effective dose can be obtained by extrapolating the dose-response curve derived from in vitro or animal model test systems.

The compound of the present invention can also be formulated in combination with one or more other active ingredients, such other active ingredients including any pharmaceutical agents, such as antiviral agents, vaccines, antibodies, immune enhancers, immunosuppressants, anti-inflammatory agents and the like.

Example Equipment: Bruker AVANCE 300 MHz/400 MHz spectrometer was used to record ¹ H NMR spectra at 300 or 400 MHz. Use Bruker Topsin software to perform NMR interpretation to assign chemical shifts and multiple peaks. In the case where two adjacent peaks of equal or unequal height are observed, the two peaks can be marked as multiplets or doublets. In the case of double peaks, you can assign the coupling constant using this software. In any given instance, one or more protons may not be observed due to the ambiguity of the water and/or solvent peaks. LCMS equipment and conditions are as follows: 1. LC (alkaline conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Kinetex 2.6 μm EVO C18 100A, 50*3.0 mm, 2.6 μm. Mobile phase: A: water/5 mM NH ₄ HCO ₃ , B: acetonitrile. Flow rate: 1.2 mL/min at 40°C. Detector: 254 nm, 220 nm. Gradient end time, 2.9 min. Timetable: T (min) A(%) B(%) 0.01 90 10 2.10 5 95 2.70 5 95 2.90 90 10 2. LC (alkaline conditions): Shimadzu LC-20ADXR, binary pump, diode array detector, column: Poroshell HPH-C18 50*3.0 mm, 2.7 µm. Mobile phase A: 0.04% ammonium hydroxide, mobile phase B: acetonitrile. Flow rate: 1.2 ml/min at 40°C. Detector: 254 nm, 220 nm. Gradient end time 3.0 min Timetable: T(min) A(%) B(%) 0.01 90 10 2.0 5 95 2.7 5 95 2.8 90 10 3. LC (acidic conditions): Shimadzu LC-20AD, binary pump, diode array detector. Column: Ascentis Express C18, 50*3.0 mm, 2.7 µm. Mobile phase: A: water/0.05% TFA, B: acetonitrile/0.05% TFA. Flow rate: 1.5 mL/min at 40°C. Detector: 254 nm, 220 nm. Gradient end time, 2.9 min. Timetable: T (min) A(%) B(%) 0.01 90 5 2.10 5 95 2.70 5 95 2.90 90 5 4. LC (acidic conditions): Shimadzu LC-30AD, binary pump, diode array detector. Column: Accucore C18 50*2.1 mm, 2.6 µm. Mobile phase A: water/0.1% FA, mobile phase B: acetonitrile/0.1% FA. Flow rate: 1.0 ml/min at 40°C. Detector: 254 nm, 220 nm. Gradient end time 3.0 min. Timetable: T(min) A(%) B(%) 0.01 95 5 2.0 5 95 2.7 5 95 2.8 95 5 1. S: LCMS-2020, quadrupole LC/MS, ion source: ES-API, TIC: 90~900 m/z, breaker: 60, drying air flow: 15 L/min, atomizing air flow: 1.5 L /min, dry gas temperature: 250℃, Vcap: 1100V. 2. Sample preparation: Dissolve the sample in ACN or methanol at 1-10 mg/mL, and then filter it through a 0.22 μm filter membrane. Injection volume: 1~10 μL.

Definition : ACN (acetonitrile); CH ₃ CN (acetonitrile); CDCl ₃ (deuterated chloroform); CD ₃ OD (deuterated methanol); DCM (dichloromethane); DEA (diethylamine); DIEA (diisopropyl) Ethylamine); DMF ( N , N -dimethylformamide); DMAP (4-dimethylaminopyridine); DMSO (dimethyl sulfide); DMSO- d ₆ (deuterated dimethyl sulfide) ); equiv (equivalent); ESI (electrospray ionization); EtOAc (ethyl acetate); EtOH (ethanol); g (gram); h (hour); HATU (hexafluorophosphoric acid 1-[bis(dimethyl Amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide); ¹ H NMR (proton nuclear magnetic resonance); HCl (hydrochloric acid); Hz ( Hertz); H ₂ O (water); Hex (hexane); i-prOH (isopropanol); K ₂ CO ₃ (potassium carbonate); L (liter); LCMS (liquid chromatography-mass spectrometry); M (Molar concentration); MeCN (acetonitrile); MeOH (methanol); mg (mg); MHz (megahertz); min (minutes); MtBE (methyl tertiary butyl ether); mL (ml), mmol ( Millimoles); N (nominal); NaBH(AcO) ₃ (sodium triacetoxyborohydride); NaCl (sodium chloride); NaH (sodium hydride); NaHCO ₃ (sodium bicarbonate); n- BuOH (n-butyl alcohol); NH ₄ Cl (ammonium chloride); NMP (N-methyl-2-pyrrolidone); PE (petroleum ether); PMB (p-methoxybenzyl); prep-HPLC (Preparative high performance liquid chromatography); RT (room temperature) ; TEA (triethylamine) ; TFA (trifluoroacetic acid); tR (retention time); triflic (trifluoromethanesulfonic acid); AcOH (acetic acid); HATU (hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide); Na ₂ CO ₃ (sodium carbonate); NaBH ₃ CN (sodium cyanoborohydride); NaOH (sodium hydroxide); NH ₃ (ammonia); Pd/C (palladium on carbon); PMB (p-methoxybenzyl); STAB (Sodium triacetoxyborohydride); t-BuOK (potassium tertiary butoxide); TEMPO ((2,2,6,6-tetramethylhexahydropyridin-1-yl)oxy); Tf ₂ O (trifluoromethanesulfonic anhydride); TfOH (trifluoromethanesulfonic acid); THF (tetrahydrofuran); Ti(Oi-Pr) ₄ (titanium isopropoxide).

Intermediate I-1: 5- chloro-2- (4-methoxybenzyl) (trifluoromethyl) despair 𠯤 -3 (2H) -4- - one Synthesis of

Step A Divide 4,5-dibromo-2,3-dihydrod-3-one (250 g, 984.71 mmol, 1 equiv) in DMF (2.5 L) at 0-10℃. NaH (59.1 g, 1477.07 mmol, 1.50 equiv, 60%) was added in batches, followed by 1-(chloromethyl)-4-methoxybenzene (230.3 g, 1470.53 mmol, 1.49 equiv) at 0°C. The resulting solution was stirred at RT for 3 h. The reaction was then quenched by adding 5 L ice/water and extracted with 2 x 2.5 L DCM. The organic layers were combined and concentrated. The solid was washed with MeOH (500 mL × 2) to obtain 290 g (79% yield) of solid 4,5-dibromo-2-[(4-methoxyphenyl)methyl]-2, 3-Dihydrota 𠯤-3-one. LCMS [M+H] ⁺ 378.00.

Step B Combine 4,5-dibromo-2-[(4-methoxyphenyl)methyl]-2,3-dihydrogen-3-one (290 g, 775.33 mmol, 1 equiv) and hydrogen A solution of potassium oxide (130.5 g, 2326.00 mmol, 3.00 equiv) in MeOH (2.5 L) was stirred at RT for 2 h. The resulting mixture was concentrated to 500 mL and the solid was collected by filtration. The obtained cake was slurried in water (1L) for 1 h to obtain 232 g (92% yield) of solid 4-bromo-5-methoxy-2-[(4-methoxyphenyl)methyl基]-2,3-dihydrota 𠯤-3-one. LCMS [M+H] ⁺ 326.90.

Step C: The 4-bromo-5-methoxy-2-[(4-methoxyphenyl)methyl]-2,3-dihydrogen-3-one (232 g, 713.49 mmol, 1 equiv ), 2,2-difluoro-2-sulfoacetic acid methyl ester (411.2 g, 2140.44 mmol, 3.00 equiv) and CuI (67.9 g, 356.52 mmol, 0.50 equiv) in NMP (1.2L) solution at 100℃ Stir for 3 h. The reaction was then quenched by adding 1.5 L of water. The resulting solution was extracted with 3 x 1L DCM. The organic layers were combined and concentrated. The residue was applied to a silica gel column with EtOAc/petroleum ether (1/1). The collected fractions were combined and concentrated to obtain crude oil, to which 1 L of water was added. The solid was collected by filtration and washed with 100 mL MeOH to obtain 170 g (76% yield) of solid 5-methoxy-2-[(4-methoxyphenyl)methyl]-4-( (Trifluoromethyl)-2,3-dihydro-taka-3-one. LCMS [M+H] ⁺ 315.10.

Step D: Add 5-methoxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydrogen-3-one at 20°C (170 g, 540.95 mmol, 1 equiv) in DMF (850 mL) was added dropwise TMSI (140 g, 699.67 mmol, 1.29 equiv). The resulting solution was stirred at 85°C for 20 h. Then the reaction mixture was quenched by adding 850 mL water and the resulting solution was extracted with 3×850 mL DCM and the organic layers were combined and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum and the crude product was purified by silica gel column chromatography and then recrystallized with MtBE to obtain 120 g (74% yield) of 5-hydroxy-2-[(4-methoxy (Phenyl)methyl]-4-(trifluoromethyl)-2,3-dihydrota 𠯤-3-one. LCMS [M+H] ⁺ 301.07.

Step E: Add 5-hydroxy-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydrogen-3-one at 0-5℃ (110 g, 366.38 mmol, 1 equiv) in DMF (550 mL) was added dropwise oxalate dichloride (93 g, 732.75 mmol, 2.00 equiv). The resulting solution was stirred at RT for 8 h. The reaction was then quenched by adding 550 mL of water. The solid was collected by filtration to obtain 108 g (93%) of 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3 as a white solid -Dihydrota 𠯤-3-one. LCMS [M+H] ⁺ 319.04 [M+H] ⁺ , ¹ H NMR (30 MHz, DMSO- d ₆ ) δ 8.22 (d, J = 0.8 Hz, 1H), 7.33 – 7.22 (m, 2H), 6.94 – 6.84 (m, 2H), 5.18 (s, 2H), 3.71 (s, 3H).

Intermediate I-2 : (S)-2-(2-((1-(4 -methoxybenzyl )-6- pendant oxy -5-( trifluoromethyl )-1,6 -dihydro despair 𠯤 4-yl) amino) propoxy) synthesis of acetic acid

Step A To a solution of (S)-(1-hydroxyprop-2-yl)carbamic acid tert-butyl ester (5.00 g, 28.5 mmol, 1.0 equiv) in DMF (80 mL) at 0°C in batches Add NaH (60% dispersion in oil, 3.4 g, 85.6 mmol, 3.0 equiv). The mixture was stirred at this temperature for 20 min and to this suspension was added tert-butyl 2-bromoacetate (7.30 g, 57 mmol, 2.00 equiv). The resulting solution was stirred at 0°C for 30 min and then water (60 mL) was added. The solution was extracted with 3 × 100 mL ethyl acetate. The organic layers were combined and washed with 3×50 mL brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (3:7) to obtain 2.8 g (34% yield) of colorless oil (S)-2-(2-(( The tertiary butoxycarbonyl) amino) propoxy) tertiary butyl acetate. LCMS (ESI, m/z): 290.20 [M+H] ⁺ .

Step B: Combine 2-[(2S)-2-[(Third-butoxycarbonyl)amino]propoxy]acetate (2.80 g, 9.7 mmol, 1.0 equiv) in 4N dioxane The solution in HCl (30 mL) was stirred at room temperature for 14 hours. The mixture was concentrated to obtain 2.5 g of crude (S)-2-(2-aminopropoxy)acetic acid hydrochloride as a red oil. LCMS (ESI, m/z): 133.15 [M+H] ⁺ .

In step C, 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)- 3(2H)-one (3.00 g, 9.4 mmol, 1.00 equiv; Intermediate I- 1), TEA (2.86 g, 28.2 mmol, 3.0 equiv) and (S)-2-(2-aminopropoxy)acetic acid hydrochloride (2.50 g, 14.7 mmol, 1.6 equiv) in i-PrOH (100 The solution in mL) was stirred at 60°C for 2 hours. The mixture was concentrated and the crude product was applied to a silica gel column eluted with dichloromethane/methanol (10:1) to obtain 1.9 g (49% yield) of (S)-2-(2- ((1-(4-Methoxybenzyl)-6-Pendoxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy)acetic acid . LCMS (ESI, m/z): 415.2 [M+H] ⁺ .

Intermediate I-3 : Synthesis of 3- hydroxy- 1-( hexahydropyridin- 4 -yl ) pyrrolidin -2- one hydrochloride

Step A : Combine 2-(2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)acetaldehyde (6.00 g, 37.9 mmol, 1.0 equiv), acetic acid (2.73g , 45.5 mmol, 1.2 equiv) and 4-aminohexahydropyridine-1-tert-butyl acetate (15.2 g, 75.9 mmol, 2.0 equiv) in DCE (100 mL) were stirred for 1 hour and then STAB ( 24.0 grams, 114 mmol, 3.0 equiv). The resulting solution was stirred at room temperature for 14 hours. Adjust the pH value of the solution to 8 with saturated aqueous sodium bicarbonate solution. The resulting solution was extracted with 3 × 100 mL of dichloromethane. The organic layers were combined and washed with 50 mL 10% aqueous citric acid solution and 50 mL brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate/petroleum ether (8:2) to produce 5.1 g (47% yield) of 4-(3-hydroxy-2-oxo) as a yellow solid Pyrrolidin-1-yl) hexahydropyridine-1-acetic acid tert-butyl ester. LCMS (ESI, m/z): 285.2 [M+H] ⁺ .

Step B: Combine 4-(3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetate (2.0 g, 1.0 equiv) in 4N HCl (30 The solution in mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated to obtain 1.8 g of crude 3-hydroxy-1-(hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride as a white solid, which was used without further purification. LCMS (ESI, m/z): 185.1 [M+H] ⁺ .

Intermediate I-4 : Synthesis of N- methyl- 1-(5-( trifluoromethyl ) thiazol- 2- yl ) hexahydropyridine- 4- amine

Step A: Tributyl methyl(hexahydropyridin-4-yl)carbamate (214 mg, 0.99 mmol, 1.0 equiv), 2-bromo-5-(trifluoromethyl)thiazole (232 mg, 0.99 A solution of K ₂ CO ₃ (207 mg, 1.49 mmol, 1.5 equiv) in NMP (5 mL) was stirred at 80°C for 2 hours. Water (20 mL) was added and the resulting solution was extracted with 3×15 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (2/3) to obtain 343 mg (94% yield) of methyl (1-(5-(trifluoro) (Methyl)thiazol-2-yl)hexahydropyridin-4-yl)carbamic acid tert-butyl ester. LCMS (ESI, m/z): 366.1 [M+H] ⁺ .

( N-甲基-1-(5-(三氟甲基)嘧啶-2-基)氮雜環丁-3-胺鹽酸鹽 LCMS (ESI, m/z): 233.25 [M+H]⁺ I-6   

N-甲基-1-(5-(三氟甲基)吡𠯤-2-基)六氫吡啶-4-胺鹽酸鹽    LCMS (ESI, m/z): 261.1 [M+H]⁺ Step B: Combine tert-butyl methyl (1-(5-(trifluoromethyl)thiazol-2-yl)hexahydropyridin-4-yl)carbamate (343 mg, 0.94 mmol, 1.00 equiv) in two The solution in 4N HCl (5 mL) in oxane was stirred for 1 hour and then the mixture was concentrated to obtain 275 mg (97% yield) of N-methyl-1-(5-(trifluoromethyl) as a white solid ) Thiazol-2-yl)hexahydropyridine-4-amine hydrochloride. LCMS (ESI, m/z): 266.00 [M+H] ⁺ . Intermediates I-5-I-6 are based on the synthesis of N-methyl-1-(5-(trifluoromethyl)thiazol-2-yl)hexahydropyridin-4-amine (Intermediate I-4) The described procedure may be synthesized using appropriate construction components and modified reaction conditions (such as reagent ratio, temperature, coupling conditions, and reaction time) as needed. Intermediate Number structure analyze data I-5

( N-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)azetidin-3-amine hydrochloride LCMS (ESI, m/z): 233.25 [M+H] ⁺ I-6

N-methyl-1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridine-4-amine hydrochloride LCMS (ESI, m/z): 261.1 [M+H] ⁺

Example 1 : (S)-2-(2-(6 -Pendant oxy -5-( trifluoromethyl )-1,6- dihydrothia- 4 - ylamino) propoxy )-N- Synthesis of (1-(5-( Trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl ) acetamide

Step A: Combine tert-butyl hexahydropyridin-4-ylcarbamate (2.00 g, 9.98 mmol, 1.0 equiv), 2-chloro-5-(trifluoromethyl)pyrimidine (1.82 g, 9.99 mmol, 1.0 equiv) ) And a solution of K ₂ CO ₃ (1.38 g, 9.99 mmol, 1.0 equiv) in NMP (50 mL) was stirred at 80°C for 2 hours. Water (200 mL) was added and the solid was collected by filtration to obtain tert-butyl 1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-ylcarbamate ( 3.7 g, 96% yield, 90% purity). LCMS (ESI, m/z): 347.15 [M+H] ⁺ .

Step B: Combine 1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-ylcarbamate (2.31 g, 6.0 mmol, 1.0 equiv, 90% purity) in 1 The solution in 4N HCl (20 mL) in 4-dioxane was stirred at room temperature for 1 hour. The solid was collected by filtration to obtain 1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine hydrochloride (1.27 g, 82% yield) as a white solid. LCMS (ESI, m/z): 247.20 [M+H] ⁺ .

Step C: Add (S)-2-(2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydro 4-yl)amino)propoxy)acetic acid (200 mg, 0.48 mmol, 1.0 equiv, 50% purity; Intermediate I-2), DIEA (187 mg, 1.44 mmol, 3.0 equiv), HATU (183 mg, 0.48 mmol, 1.0 equiv) and 1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine hydrochloride (119 mg, 0.48 mmol, 1.0 equiv) in DMF (2.0 mL) The solution in it was stirred at room temperature for 1 hour. After concentration, the residue was applied to a _{reversed-phase column eluted with H 2} O/CH ₃ CN (31/69) to obtain (S)-2-(2-(1-(4- (Methoxybenzyl)-6-Pendoxy-5-(trifluoromethyl)-1,6-dihydrotetrakis-4-ylamino)propoxy)-N-(1-(5- (Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide (51 mg, 15% yield). LCMS (ESI, m/z): 644.20 [M+H] ⁺ .

Step D at 0℃ to (S)-2-(2-(1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydro (4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide (49 mg, 0.076 mmol, 1.0 equiv) Trifluoromethanesulfonic acid (0.10 mL) was added to the solution in TFA (1.00 mL) and the solution was maintained at this temperature for 1 hour. Ice water (30 mL) was added and the pH of the solution was adjusted to pH 7 _{with saturated aqueous NaHCO 3 solution.} The resulting solution was extracted with 3 × 60 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a _{reversed-phase column eluted with H 2} O/CH ₃ CN (50/50) to obtain (S)-2-(2-(6-terminal oxy-5- (Trifluoromethyl)-1,6-dihydrotetrakis-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine -4-yl)acetamide (14 mg, 35% yield). LCMS (ESI, m/z): 524.2 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.48 (s, 1H), 8.74 (s, 2H), 7.97 (s, 1H) , 7.58 (d, J = 8.1 Hz, 1H), 6.46 – 6.39 (m, 1H), 4.62 (d, J = 13.5 Hz, 2H), 4.22 – 4.15 (m, 1H), 4.01-3.90 (m, 2H ), 3.89 (s, 2H), 3.52 (d, J = 5.4 Hz, 2H), 3.16 (t, J = 12.2 Hz, 2H), 1.80 (d, J = 9.3 Hz, 2H), 1.42 – 1.30 (m , 2H), 1.18 (d, J = 6.6 Hz, 3H).

Example 2 : (S)-N- Methyl -2-(2-(6 -Pendant oxy -5-( trifluoromethyl )-1,6- dihydrothia- 4 - ylamino) propoxy Synthesis of yl )-N-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl ) acetamide

Step A Add 1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-ylaminocarboxylate (2.31 g, 6.67 mmol, 1.00 equiv) at 0°C; Example 1 , Step A) The solution in DMF is treated with NaH (800 mg, 20.0 mmol, 3.0 equiv, 60% dispersion in mineral oil). After 15 minutes, methyl iodide (0.95 g, 6.67 mmol, 1.0 equiv) was added and the solution was stirred at room temperature for 1 hour. Add 50 mL of water and collect the solid by filtration to obtain tertiary methyl (1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)aminocarboxylic acid as a white solid Ester (1.65 g, 63% yield). LCMS (ESI, m/z): 361.20 [M+H] ⁺ .

Step B : Mix tert-butyl methyl (1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)carbamate (1.65 g, 4.578 mmol, 1.00 equiv) in 1 The solution in 4N HCl (16 mL) in 4-dioxane was stirred at room temperature for 1 h. The solid was collected by filtration to obtain N-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine hydrochloride (1.21 g, 96% yield) as a white solid Rate). LCMS (ESI, m/z): 261.20 [M+H] ⁺ .

Step C (S)-2-(2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydro 4-yl)amino)propoxy)acetic acid (200 mg, 0.48 mmol, 1.0 equiv; Intermediate I-2), N-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl )Hexahydropyridine-4-amine hydrochloride (125 mg, 0.48 mmol, 1.0 equiv), DIEA (187 mg, 1.44 mmol, 3.0 equiv) and HATU (183 mg, 0.48 mmol, 1.0 equiv) in DMF (2 mL The solution in) was stirred at room temperature for 1 hour. After concentration, the residue was applied to a _{reversed-phase column eluted with H 2} O/CH ₃ CN (26/74) to obtain (S)-2-(2-(1-(4- (Methoxybenzyl)-6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotetrakis-4-ylamino)propoxy)-N-methyl-N-( 1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide (117 mg, 29% yield). LCMS (ESI, m/z): 658.25 [M+H] ⁺ .

(S)-N-甲基-2-(2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)-N-(1-(5-(三氟甲基)噻唑-2-基)六氫吡啶-4-基)乙醯胺 LCMS (ESI, m/z): 543.20 [M+H]⁺ ；¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.46 (s, 1H), 7.92 (s, 1H), 7.70 (t,J = 1.5 Hz, 1H), 6.79 – 6.59 (m, 1H), 4.57 – 4.42(m, 1H), 4.29 (s, 1H), 4.25 – 4.15 (m, 2H), 4.02 - 3.91 (m, 2H), 3.55 – 3.48 (m, 2H), 3.27 – 3.12(m, 2H), 2.68 (d,J = 8.7 Hz, 3H), 1.91 – 1.62 (m, 3H), 1.61 – 1.55 (m, 1H), 1.16 (d,J = 6.4 Hz, 3H)。 4   

(S)-N-甲基-2-(2-(6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基胺基)丙氧基)-N-(1-(5-(三氟甲基)吡𠯤-2-基)六氫吡啶-4-基)乙醯胺 LCMS (ESI, m/z): 538.20 [M+H]⁺ ；¹ H NMR (300 MHz, DMSO-d₆ )δ 12.47 (s, 1H), 8,47 (d,J = 1.8 Hz,  2H), 7.95 (s, 1H), 6.73 - 6.50(m, 1 H), 4.62 - 4.58 (m, 3 H), 4.34 - 4.19(m, 3 H), 3.61 – 3.54 (m, 2H), 3.10 – 2.91 m, 2 H), 2.68 (d,J = 9.3 Hz, 3H), 1.71 -1.60 (m, 4H), 1.18 (d,J = 6.2 Hz, 3H)。 5

((S)-N-甲基-2-(2-(6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基胺基)丙氧基)-N-(1-(5-(三氟甲基)嘧啶-2-基)氮雜環丁-3-基)乙醯胺 LCMS (ESI, m/z): 510.20；¹ H NMR (400 MHz, DMSO-d₆ ) δ 12.48 (s, 1H), 8.71 (s, 2H), 7.95 (s, 1H), 6.80 - 6.71 (m, 1H), 5.34 – 5.24 (m, 1H), 4.45 – 4.15 (m, 7H), 3.54 (d,J = 5.9 Hz, 2H), 2.96 (s, 3H), 1.17 (d,J = 6.5 Hz, 3H)。 Step D Add (S)-2-(2-(1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydro at 0°C (4-ylamino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide A solution of (115 mg, 0.18 mmol, 1.0 equiv) in TFA (2.00 mL) was treated with trifluoromethanesulfonic acid (0.20 mL) and maintained at this temperature for 20 min. Ice water (30 mL) was added and the pH of the solution was adjusted to pH 7 _{with saturated aqueous NaHCO 3 solution.} The resulting solution was extracted with 3 × 100 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a _{reverse phase column eluted with H 2} O/CH ₃ CN (42/58) to obtain (S)-N-methyl-2-(2-(6-side) as a white solid Oxy-5-(trifluoromethyl)-1,6-dihydrotetra-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidine-2- (Yl)hexahydropyridin-4-yl)acetamide (18 mg, 19% yield). LCMS (ESI, m/z): 538.2 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.22 (s, 1H), 8.65 (s, 2H), 7.89 (s, 1H) , 6.75 – 6.50 (br, 1H), 4.86 (d, J = 12.6 Hz, 2H), 4.60 – 4.40 (rottamers A, m, 1H), 4.30 (s, 1H), 4.22 – 4.12 (m, 3H), 3.85-3.79 (rotamers B, m, 1H). 3.52 – 3.48 (m, 2H), 3.10 – 2.89 (m, 2H), 2.65 – 2.72 (m, 3H), 1.80 – 1.50 (m, 4H), 1.23 (d, J = 6.6 Hz, 3H). Examples 3-5 are based on Yl)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide (see Example 2), It can be synthesized using appropriate construction components and modified reaction conditions (such as reagent ratio, temperature, coupling conditions, and reaction time) as needed. Instance number structure analyze data 3

(S)-N-Methyl-2-(2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)amino)propoxy )-N-(1-(5-(Trifluoromethyl)thiazol-2-yl)hexahydropyridin-4-yl)acetamide LCMS (ESI, m/z): 543.20 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.46 (s, 1H), 7.92 (s, 1H), 7.70 (t, J = 1.5 Hz, 1H), 6.79 – 6.59 (m, 1H), 4.57 – 4.42(m, 1H), 4.29 (s, 1H), 4.25 – 4.15 (m, 2H), 4.02-3.91 (m, 2H), 3.55 – 3.48 (m, 2H), 3.27 – 3.12(m, 2H), 2.68 (d, J = 8.7 Hz, 3H), 1.91 – 1.62 (m, 3H), 1.61 – 1.55 (m, 1H), 1.16 (d , J = 6.4 Hz, 3H). 4

(S)-N-Methyl-2-(2-(6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-ylamino)propoxy)- N-(1-(5-(Trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)acetamide LCMS (ESI, m/z): 538.20 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.47 (s, 1H), 8,47 (d, J = 1.8 Hz, 2H) , 7.95 (s, 1H), 6.73-6.50(m, 1 H), 4.62-4.58 (m, 3 H), 4.34-4.19(m, 3 H), 3.61-3.54 (m, 2H), 3.10-2.91 m, 2 H), 2.68 (d, J = 9.3 Hz, 3H), 1.71 -1.60 (m, 4H), 1.18 (d, J = 6.2 Hz, 3H). 5

((S)-N-Methyl-2-(2-(6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-ylamino)propoxy) -N-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)azetidin-3-yl)acetamide LCMS (ESI, m/z): 510.20; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1H), 8.71 (s, 2H), 7.95 (s, 1H), 6.80-6.71 (m , 1H), 5.34 – 5.24 (m, 1H), 4.45 – 4.15 (m, 7H), 3.54 (d, J = 5.9 Hz, 2H), 2.96 (s, 3H), 1.17 (d, J = 6.5 Hz, 3H).

Example 6: (S) -N- (1- (5- cyano-pyridin-2-yl) -piperidin-4-yl) -N- methyl-2- (2 - ((6-oxo - 5- (trifluoromethyl) -1,6-dihydropyridazine 𠯤 4-yl) amino) propoxy) as acetamide synthesis of

Step A : Combine tert-butyl methyl(hexahydropyridin-4-yl)carbamate (1.00 g, 4.666 mmol, 1.00 equiv), 6-chloronicotine carbonitrile (0.52 g, 3.733 mmol, 0.80 equiv) and A solution of K ₂ CO ₃ (0.64 g, 4.666 mmol, 1.0 equiv) in NMP (50 mL) was stirred at 80°C for 2 hours. 150 mL of water was added and the solid was collected by filtration to obtain (1-(5-cyanopyridin-2-yl)hexahydropyridin-4-yl)(methyl)carbamic acid tert-butyl ester ( 970 mg, 59% yield). LCMS: (M+H) ⁺ : 317.10.

Step B: (1-(5-Cyanopyridin-2-yl)hexahydropyridin-4-yl)(methyl)carbamic acid tert-butyl ester (960 mg, 3.034 mmol, 1.00 equiv) in 1,4 -A solution of 4N HCl (20 mL) in dioxane was stirred at room temperature for 1 h. The solution was concentrated to obtain 6-(4-(methylamino)hexahydropyridin-1-yl)nicotine carbonitrile hydrochloride (810 mg, 99% yield) as a yellow oil. LCMS: (M+H) ⁺ : 217.20.

Step C: Add (S)-2-(2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydro 4-yl)amino)propoxy)acetic acid (77 mg, 0.185 mmol, 1.00 equiv; intermediate 1-2), 6-(4-(methylamino)hexahydropyridin-1-yl)nicotine A solution of formonitrile hydrochloride (26 mg, 0.120 mmol, 0.65 equiv), DIEA (23 mg, 0.185 mmol, 1 equiv) and HATU (46 mg, 0.120 mmol, 0.65 equiv) in DMF (2 mL) was stirred 1 Hour. After concentration, the residue was applied to a _{reversed-phase column eluted with H 2} O/CH ₃ CN (37/63) to obtain (S)-N-(1-(5-cyanopyridine) as a yellow oil -2-yl)hexahydropyridin-4-yl)-2-(2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1, 6-Dihydrothia-4-yl)amino)propoxy)-N-methylacetamide (51 mg, 43% yield). LCMS: (M+H) ⁺ : 614.25.

Step D Add (S)-N-(1-(5-cyanopyridin-2-yl)hexahydropyridin-4-yl)-2-(2-((1-(4-methoxy (Benzyl)-6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota (4-yl)amino)propoxy)-N-methylacetamide (50 mg, 0.081 mmol, 1.00 equiv) To a solution of TFA (1.00 mL) was added trifluoromethanesulfonic acid (0.10 mL) and the mixture was stirred at this temperature for 1 hour. Ice water (30 mL) was added and the pH of the solution was adjusted to 7 _{with saturated aqueous NaHCO 3 solution.} The resulting solution was extracted with 3 × 60 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a _{reverse phase column eluted with H 2} O/CH ₃ CN (51/49) to obtain (S)-N-(1-(5-cyanopyridine-2- Yl)hexahydropyridin-4-yl)-N-methyl-2-(2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-4-yl ) Amino) Propoxy) Acetamide (15 mg, 36% yield). LCMS: (M+H) ⁺ : 494.20. ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.48 (s, 1H), 8.48 (d, J = 3.0 Hz, 1H), 7.95 (s, 1H), 7.83 (dd, J = 9.3, 2.4 Hz, 1H), 6.97 (d, J = 9.1 Hz, 1H), 6.73 – 6.65 (m, 1H), 4.71 – 4.50 (m, 2H), 4.33 (s, 1H), 4.15(s, 2H), 3.80 -3.75 (m, 1H), 3.60 -3.50 (m, 2H), 3.01 – 2.88 (m, 2H), 2.67 (d, J = 9.6 Hz, 3H), 1.78 – 1.52 (m, 4H), 1.18 (d, J = 6.4 Hz, 3H).

Example 7 : (S)-N- Ethyl -2-(2-((6 -Pendant oxy -5-( trifluoromethyl )-1,6- dihydrothia- 4 -yl ) amino ) Synthesis of propoxy )-N-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl ) acetamide

Step A will (S)-2-(2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydro 4-yl)amino)propoxy)acetic acid (414 mg, 1.0 mmol, 1.0 equiv; Intermediate I-2), HATU (380 mg, 1.0 mmol, 1.0 equiv), DIEA (260 mg, 2 mmol, 2.00 Equiv) and 4-(ethylamino)hexahydropyridine-1-acetic acid tert-butyl ester (230 mg, 1.0 mmol, 1.0 equiv) in DMF (4 mL) were stirred at room temperature for 1 hour. The residue was purified by reverse phase chromatography eluted with H ₂ O/CH ₃ CN to obtain 200 mg (32% yield) of (S)-4-(N-ethyl-2-( 2-((1-(4-Methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)amino)propoxy )Acetamido)hexahydropyridine-1-tert-butyl acetate. LCMS (ESI, m/z): 626.25 [M+H] ⁺ .

Step B will (S)-4-(N-ethyl-2-(2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1 ,6-Dihydropyridine-4-yl)amino)propoxy)acetamido)hexahydropyridine-1-acetate (200 mg, 0.32 mmol, 1.0 equiv) in dioxane The solution in 4N HCl (5 mL) was stirred at room temperature for 2 hours. The solution was concentrated under vacuum to obtain 130 mg (78% yield) of (S)-N-ethyl-2-(2-((1-(4-methoxybenzyl)-6- Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy)-N-(hexahydropyridin-4-yl)acetamide hydrochloride Salt, which was used without further purification. LCMS (ESI, m/z): 526.25 [M+H] ⁺ .

Step C will (S)-N-ethyl-2-(2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6- Dihydropyridine-4-yl)amino)propoxy)-N-(hexahydropyridin-4-yl)acetamide (130 mg, 0.25 mmol, 1.0 equiv), K ₂ CO ₃ (104 mg, A solution of 0.75 mmol, 3.0 equiv) and 2-chloro-5-(trifluoromethyl)pyrimidine hydrochloride (46 mg, 0.25 mmol, 1.0 equiv) in DMF (5 mL) was stirred at room temperature for 2 hours. Water was added, and the resulting solution was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by reverse phase chromatography eluted with H ₂ O/CH ₃ CN to obtain 140 mg (83% yield) of (S)-N-ethyl-2-(2-( (1-(4-Methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy)-N -(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide. LCMS (ESI, m/z): 672.25 [M+H] ⁺ .

In step D , (S)-N-ethyl-2-(2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)- 1,6-Dihydropyridine-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)ethyl A solution of amide (140 mg, 0.21 mmol, 1.00 equiv) in trifluoroacetic acid (3 mL) was treated with trifluoromethanesulfonic acid (0.3 mL) and maintained at this temperature for 1 hour. Water was added and the pH was adjusted to 6 _{with saturated aqueous Na 2} CO _{3 solution.} The resulting solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude residue was purified by reverse phase chromatography eluted with H ₂ O/CH ₃ CN to obtain 80 mg (69% yield) of (S)-N-ethyl-2-(2- ((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl) (Yl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide. LCMS (ESI, m/z): 552.20 [M+H] ⁺ ; ¹ HNMR (DMSO- d ₆ , 300 MHz) δ 12.47 (s, 1H), 8.69 (s, 2H), 7.93 (s, 1H), 6.75 – 6.68 (m, 1H), 4.82 (d, J = 13.1 Hz, 2H), 4.27 (s, 1H), 4.18 (d, J = 3.5 Hz, 2H), 3.80 – 3.71 (m, 1H), 3.56 (d, J = 5.6 Hz, 2H), 3.15 (d, J = 7.3 Hz, 2H), 3.01 – 2.89 (m, 2H), 1.78 – 1.62 (m, 4H), 1.18 (t, J = 5.8 Hz, 3H), 1.12 – 0.93 (m, 3H).

Example 8 : (S)-N- Methyl- 2-((1-(6 -Pendant oxy -5-( trifluoromethyl )-1,6- dihydrothia- 4 -yl ) azaheterocycle Synthesis of But- 2- yl ) Methoxy )-N-(1-(5-( Trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl ) acetamide

Step A : Combine (S)-azetidin-2-ylmethanol hydrochloride (1.20 g, 9.71 mmol, 1.0 equiv), TEA (2.80 mL) and 5-chloro-2-(4-methoxybenzyl) )-4-(trifluoromethyl)pada-3(2H)-one (3.20 g, 10.0 mmol, 1.03 equiv; Intermediate I-1) in ethanol (20 mL) was stirred at 60°C for 1 h. After cooling to room temperature, the solution was removed under vacuum. The crude product was purified by reversed-phase chromatography eluted with H ₂ O/CH ₃ CN to obtain 2.0 g (55% yield) of (S)-5-(2-(hydroxymethyl)nitrogen) as a white solid Etan-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl)taka-3(2H)-one. LCMS (ESI, m/z): 370.15 [M+H] ⁺ .

Step B: (S)-5-(2-(hydroxymethyl)azetidin-1-yl)-2-(4-methoxybenzyl)-4-(trifluoromethyl) 3(2H)-ketone (738 mg, 1.99 mmol, 1.0 equiv), tert-butyl 2-chloroacetate (604 mg, 4.01 mmol, 2.01 equiv) and NaH (60% dispersion in oil, 240 mg, 6.0 A solution of (mmol, 3.0 equiv) in DMF (10 mL) was stirred at 0°C for 2 hours. After concentration, the _{residue was purified by C18 reverse phase chromatography eluted with H 2} O/CH ₃ CN to obtain (S)-2-((1-(1-(4-methoxybenzyl) as a yellow oil )-6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)azetidin-2-yl)methoxy)tert-butyl acetate 430 mg (44% yield). LCMS (ESI, m/z): 483.15 [M+H] ⁺ .

Step C Add (S)-2-((1-(1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydro 4-yl)azetidin-2-yl)methoxy)tert-butyl acetate (420 mg, 0.87 mmol, 1.0 equiv) in TFA (5 mL) and DCM (5 mL) at room temperature Stir for 2 hours and concentrate the solution to obtain 490 mg (92% yield) of (S)-2-((1-(1-(4-methoxybenzyl)-6-oxo-5 -(Trifluoromethyl)-1,6-dihydrota-4-yl)azetidin-2-yl)methoxy)acetic acid. LCMS (ESI, m/z): 428.10 [M+H] ⁺ .

Step D will (S)-2-((1-(1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydro 4-yl)azetidin-2-yl)methoxy)acetic acid (274 mg, 1.05 mmol, 1.0 equiv), DIEA (408 mg, 3.16 mmol, 3.0 equiv) and HATU (600 mg, 1.58 mmol, 1.5 A solution of equiv) in DMF (5 mL) was stirred at room temperature for 1 hour. The residue was directly purified by reverse phase chromatography eluted with H ₂ O/CH ₃ CN to yield 533 mg of (S)-2-((1-(1-(4-methoxybenzyl) -6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)azetidin-2-yl)methoxy)-N-methyl-N- (1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide (76% yield). LCMS (ESI, m/z): 670.20 [M+H] ⁺ .

Step E will (S)-2-((1-(1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydro 4-yl)azetidin-2-yl)methoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl ) A solution of acetamide (520 mg, 0.76 mmol, 1.0 equiv) and trifluoromethanesulfonic acid (0.33 mL) in trifluoroacetic acid (3.3 mL) was stirred at room temperature for 1 hour. Add 20 mL of water and adjust the pH of the solution to 8 _{with saturated aqueous Na 2} CO _3. The resulting solution was extracted with 3 × 15 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 reverse phase chromatography eluted with H ₂ O/CH ₃ CN to obtain 65 mg of white solid (S)-N-methyl-2-((1-(6-oxo-5 -(Trifluoromethyl)-1,6-dihydrota-4-yl)azetidin-2-yl)methoxy)-N-(1-(5-(trifluoromethyl)pyrimidine -2-yl)hexahydropyridin-4-yl)acetamide (15%). LCMS (ESI, m/z): 550.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.36 (d, J = 10.6 Hz, 1H), 8.69 (d, J = 0.9 Hz , 2H), 7.75 (s, 1H), 4.89 – 4.78 (m, 3H), 4.57 – 4.52 (m, 1H), 4.42 – 4.27 (m, 2H), 4.24 (s, 1H), 3.88 (dr, 1H) ), 3.77 (dd, J = 10.2, 4.5 Hz, 2H), 3.04 – 2.92 (m, 2H), 2.67 (d, J = 16.7 Hz, 3H), 2.49-2.41 (m, 1H), 2.11-2.01 ( m, 1H), 1.71 – 1.46 (m, 4H).

Example 9 : (S)-2-(3 -Methoxy- 2-((6 -Pendant oxy -5-( trifluoromethyl )-1,6- dihydrothia- 4 -yl ) amino group ) Propoxy )-N- methyl -N-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl ) acetamide

Step A: Combine (R)-2-amino-3-methoxyprop-1-ol hydrochloride (4.00 g, 28.3 mmol, 1.0 equiv), TEA (8.58 g, 84.8 mmol, 3.0 equiv) and 5- Chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl) 𠯤-3(2H)-one (9.00 g, 28.24 mmol, 1.0 equiv; Intermediate I-1) in i- The solution in PrOH (40 mL) was stirred at 60°C for 2 hours. The resulting mixture was concentrated under vacuum and the crude product was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (7:3) to obtain 10.5 g (96% yield) of white solid (R)-5-( (1-Hydroxy-3-methoxyprop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)taka-3(2H)-one. LCMS (ESI, m/z): 388.10 [M+H] ⁺ .

Step B at 0 ℃ (R)-5-((1-hydroxy-3-methoxyprop-2-yl)amino)-2-(4-methoxybenzyl)-4-(tri Fluoromethyl) 3(2H)-ketone (2.0 g, 5.16 mmol, 1.0 equiv) in DMF (40 mL) was added with NaH (60% dispersion in mineral oil, 207 mg, 5.16 mmol, 1.0 equiv). The solution was stirred for 15 minutes and then tert-butyl 2-bromoacetate (2.01 g, 10.33 mmol, 2.0 equiv) was added to the resulting solution. The mixture was stirred at room temperature for 1 hour. 30 mL water was added and the resulting solution was extracted with 3×50 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (1:1) to obtain 300 mg (12% yield) of (S)-2-(3-methoxy) as a yellow solid Base-2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)amino)propyl (Oxy) tertiary butyl acetate. LCMS (ESI, m/z): 502.20 [M+H] ⁺ .

Step C (S)-2-(3-methoxy-2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6 -Dihydrota-4-yl)amino)propoxy)tert-butyl acetate (240 mg, 0.48 mmol, 1.0 equiv) in trifluoroacetic acid/trifluoromethanesulfonic acid (5:1, 2.4 mL) The solution in it was stirred at room temperature for 3 hours. Water (20 mL) was added and the pH of the solution was adjusted to 8 _{with saturated aqueous NaHCO 3 solution.} The resulting solution was extracted with 3 × 50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was applied to a _{C18 reverse phase column eluted with H 2} O/CH ₃ CN (7: 3) to obtain 60 mg (39% yield) of (S)-2-(3- Methoxy-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotap-4-yl)amino)propoxy)acetic acid. LCMS (ESI, m/z): 326.10 [M+H] ⁺ .

Step D converts (S)-2-(3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)amino group )Propoxy)acetic acid (55 mg, 0.17 mmol, 1.0 equiv), N-methyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine (48 mg, A solution of 0.19 mmol, 1.10 equiv), HATU (71 mg, 0.19 mmol, 1.10 equiv) and DIEA (44 mg, 0.34 mmol, 2.0 equiv) in DMF (1 mL) was stirred at room temperature for 2 hours. 10 mL water was added and the resulting solution was extracted with 2×50 mL ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After concentration, the _{crude product was purified by reverse phase chromatography eluted with H 2} O/CH ₃ CN (45:55) to obtain 16 mg (17% yield) of (S)-2-( 3-Methoxy-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotap-4-yl)amino)propoxy)-N-methyl -N-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide. LCMS (ESI, m/z): 568.30 [M+H] ⁺ ; ¹ H NMR (DMSO- d ₆ , 300 MHz) δ 12.48 (s, 1H), 8.68 (s, 2H), 7.94 (s, 1H) , 6.70 – 6.55 (m, 1H), 4.82 (d, J = 13.2 Hz, 2H), 4.53 – 4.41 (m, 1H), 4.48 – 4.29 (m, 2H), 4.18 (s, 1H), 3.58 (d , J = 5.8 Hz, 2H), 3.47 (d, J = 5.6 Hz, 2H), 3.27 (s, 3H), 3.10 – 2.90 (m, 2H), 2.65 (d, J = 8.9 Hz, 3H), 1.80 – 1.61 (m, 4H).

Example 10 : 5-(( S )-1-(( S )-1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl )-2 -oxo yl-pyrrolidin-3-yloxy) propan-2-yl) -4- (trifluoromethyl) despair 𠯤 -3 (2 H) - one (10A) and 5 - ((S) -1- ((R) -1- (1- ( 5- ( trifluoromethyl) pyrimidin-2-yl) -piperidin-4-yl) -2-oxo-pyrrolidin-3-yloxy) propan - amino-2-yl) (trifluoromethyl) despair 𠯤 -3 (2 H) -4- - one (10B) synthesis of

In step A, 3-hydroxy-1-(hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (600 mg, 2.72 mmol, 1.0 equiv; Intermediate I-3), 2-chloro-5- A solution of (trifluoromethyl)pyrimidine (496 mg, 2.72 mmol, 1.0 equiv) and K ₂ CO ₃ (751 mg, 5.44 mmol, 2.0 equiv) in DMF (40 mL) was stirred at 60°C for 2 hours. Water (30 mL) was added and the solid was collected by filtration and dried in an oven under reduced pressure to produce 550 mg (61% yield) of white solid 1-(1-(5-(trifluoromethyl) Pyrimidine-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one. LCMS (ESI, m/z): 331.1 [M+H] ⁺ .

Step B The 1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one (550 mg, 1.67 A solution of mmol, 1.00 equiv) in DMF (60 mL) was treated with NaH (60% dispersion in oil, 200 mg, 4.99 mmol, 3.0 equiv) in portions. The mixture was stirred at 0°C for 15 min. Then (S)-4-methyl-1,2,3-oxathiazolidine-3-acetic acid tert-butyl 2,2-dioxide (593 mg, 2.5 mmol, 1.5 equiv) was added in portions. After stirring at this temperature for 1 hour, 30 mL of water was added. The resulting solution was extracted with 3 × 50 mL ethyl acetate. The organic layers were combined and washed with 3×30 mL brine. The organics were dried over anhydrous sodium sulfate and concentrated. The crude product was applied to a silica gel column eluted with ethyl acetate/hexane (9:1) to obtain 480 mg (59% yield) of (S)-1-(1-(1) as a yellow solid -(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yloxy)propan-2-ylaminocarboxylic acid tert-butyl ester. LCMS (ESI, m/z): 488.2 [M+H] ⁺ .

Step C The (S)-1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl A solution of tert-butyl oxy)propan-2-ylcarbamate (480 mg, 1.00 equiv) in 4N HCl (30 mL) in dioxane was stirred at room temperature for 1 hour. The mixture was concentrated to obtain 420 mg of 3-(( S )-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- as a yellow solid 4-yl)pyrrolidin-2-one hydrochloride. LCMS (ESI, m/z): 388.2 [M+H] ⁺ .

Step D combines 3-(( S )-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine- 2-keto hydrochloride (220 mg, 0.52 mmol, 1.0 equiv), triethylamine (157 mg, 1.56 mmol, 3.0 equiv) and 5-chloro-2-[(4-methoxyphenyl)methyl] A solution of -4-(trifluoromethyl)taka-3-one (165 mg, 0.52 mmol, 1.00 equiv) in EtOH (40 mL) was stirred at 60°C for 2 hours. After concentration, the crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (9:1) to obtain 280 mg (81% yield) of yellow oily 5-(( S )-1 -(1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yloxy)prop-2-yl Amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one. LCMS (ESI, m/z): 670.2 [M+H] ⁺ .

Step E Add 5-(( S )-1-(1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxo at 0°C yl-pyrrolidin-3-yloxy) propan-2-ylamino) -2- (4-methoxybenzyl) -4- (trifluoromethyl) despair 𠯤 -3 (2 H) - one ( A solution of 280 mg, 0.42 mmol, 1.0 equiv) in TFA (15 mL) was treated with trifluoromethanesulfonic acid (1.50 mL). After stirring for 1 hour at 0°C, the pH of the solution was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The resulting solution was extracted with 3 × 70 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by reverse phase chromatography and by chiral prep-HPLC (column: CHIRALPAK IA, 2*25cm, 5um; mobile phase A: Hex:DCM=3:1 w/10 mM NH ₃ -MeOH, Mobile phase B: EtOH; flow rate: 20 mL/min; 10% B for 14 min; 220/254 nm) for further purification to obtain isolated compounds. Assign stereochemistry based on the x-ray crystal structure of Example 10 Isomer B (10B).

Example 10 Isomer A (10A) : 5-(( S )-1-(( S )-1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4- Yl)-2-Pyrrolidin-3-yloxy)-2-ylamino)-4-(trifluoromethyl)-( 2H )-one (59 mg, 35%) , White solid). LC-MS: (ESI, m/z): 550.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.47 (s, 1H), 8.70 (s, 2H ), 7.95 (s, 1H), 6.39 – 6.30 (m, 1H), 4.85 – 4.82 (m,2H), 4.18 – 4.11 (m, 1H), 4.10 – 4.04 (dt, J = 12.7, 6.8 Hz, 2H ), 3.83 (dd, J = 10.0, 6.5 Hz, 1H), 3.61 (dd, J = 10.1, 4.7 Hz, 1H), 3.25-3.14 (m, 1H), 3.19 – 3.09 (m, 1H), 3.13- 3.01 (m, 2H), 2.31 – 2.19 (m, 1H), 1.79 – 1.55 (m, 5H), 1.18 (d, J = 6.5 Hz, 3H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50mm, 3µm; detection at 254 nm; mobile phase A: Hex:DCM=3:1 w/ 0.1% DEA, mobile phase B: EtOH, 15% mobile phase B; Flow rate: 1 mL/min; tR = 1.472 min.

Example 10 Isomer B (10B) : 5-(( S )-1-(( R )-1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4- (Pyrrolidin-3-yloxy)-2-ylamino)-4-(trifluoromethyl)-( 2H )-one (92 mg, 54%) , White solid). LC-MS: (ESI, m/z): 550.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.47 (s, 1H), 8.70 (s, 2H ), 7.95 (s, 1H), 6.39 – 6.30 (m, 1H), 4.84 – 4.81 (m, 2H), 4.18-4.08 (m, 3H), 3.83 (dd, J = 10.0, 6.5 Hz, 1H), 3.61 (dd, J = 10.1, 4.7 Hz, 1H), 3.25-3.24 (m, 1H), 3.18 – 3.11 (m, 1H), 3.10-2.98 (m, 2H), 2.31 – 2.19 (m, 1H), 1.79-1.45 (m, 5H), 1.18 (d, J = 6.5 Hz, 3H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50 mm, 3µm; detection at 254 nm; mobile phase A: Hex:DCM=3:1 w/ 0.1% DEA, mobile phase B: EtOH, 15% mobile phase B ; Flow rate: 1 mL/min; tR = 2.209 min.

於100℃下將3-((S)-2-胺基丙氧基)-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-2-酮(60 mg, 0.16 mmol, 1.0 equiv；參見實例10, 步驟C)、4,5-二氯嗒𠯤-3(2H)-酮(38 mg, 0.23 mmol, 1.5 equiv)及TEA (83 mg, 0.82 mmol, 5.3 equiv)於n-BuOH (3 mL)中之溶液攪拌15小時。藉由用H₂ O/CH₃ CN (60/40)溶析之反相管柱純化殘餘物。藉由prep-HPLC進一步純化產物，從而得到6 mg (8%產率)之白色固體狀4-氯-5-((S)-1-(2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基氧基)丙-2-基胺基)嗒𠯤-3(2H)-酮。LCMS (ESI, m/z): 516.20 [M+H]⁺ ；¹ H NMR (400 MHz, 甲醇-d₄ ) δ 8.55 (s, 2H), 7.96 (d,J = 9.9 Hz, 1H), 5.01 – 4.91 (m, 2H), 4.24 – 4.06 (m, 3H), 4.00 – 3.86 (m, 1H), 3.72 (dd,J = 9.7, 4.6 Hz, 1H), 3.41 – 3.33 (m, 1H), 3.31-3.23 (m, 1H), 3.10 – 2.97 (m, 2H), 2.42 – 2.27 (m, 1H), 1.89 – 1.87 (m, 1H), 1.85 – 1.63 (m, 4H), 1.31 (d,J = 6.6 Hz, 3H)。 Example 11 : 4- Chloro- 5-((S)-1-(2 -oxo- 1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl ) pyrrolidin-3-yloxy) propan-2-ylamino) despair 𠯤 -3 (2H) - one synthesis of

Add 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrole at 100℃ Pyridin-2-one (60 mg, 0.16 mmol, 1.0 equiv; see Example 10, step C), 4,5-dichloro- 3(2H)-one (38 mg, 0.23 mmol, 1.5 equiv) and TEA A solution of (83 mg, 0.82 mmol, 5.3 equiv) in n-BuOH (3 mL) was stirred for 15 hours. The residue was purified by a reverse phase column eluted with H ₂ O/CH _{3 CN (60/40).} The product was further purified by prep-HPLC to obtain 6 mg (8% yield) of 4-chloro-5-((S)-1-(2-oxo-1-(1-(5)) as a white solid -(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yloxy)prop-2-ylamino)pyridine-3(2H)-one. LCMS (ESI, m/z): 516.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.55 (s, 2H), 7.96 (d, J = 9.9 Hz, 1H), 5.01 – 4.91 (m, 2H), 4.24 – 4.06 (m, 3H), 4.00 – 3.86 (m, 1H), 3.72 (dd, J = 9.7, 4.6 Hz, 1H), 3.41 – 3.33 (m, 1H), 3.31 -3.23 (m, 1H), 3.10 – 2.97 (m, 2H), 2.42 – 2.27 (m, 1H), 1.89 – 1.87 (m, 1H), 1.85 – 1.63 (m, 4H), 1.31 (d, J = 6.6 Hz, 3H).

於100℃下將3-((S)-2-胺基丙氧基)-1-(1-(5-(三氟甲基)吡𠯤-2-基)六氫吡啶-4-基)吡咯啶-2-酮鹽酸鹽(90 mg, 0.212 mmol, 1.00 equiv；參見實例13, 步驟C)、4,5-二溴嗒𠯤-3(2H)-酮(54 mg, 0.213 mmol, 1.00 equiv)及Et₃ N (65 mg, 0.637 mmol, 3.00 equiv)於正丁基醇(2 mL)中之溶液攪拌3天。濃縮所得溶液且藉由用H₂ O/CH₃ CN (53/47)溶析之反相層析純化，從而得到不純期望產物。藉由prep-HPLC進一步純化產物，從而得到11 mg (9%產率)之白色固體狀4-溴-5-(((2S)-1-((2-側氧基-1-(1-(5-(三氟甲基)吡𠯤-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)胺基)嗒𠯤-3(2H)-酮。LCMS (ESI, m/z): 560.10 [M+H]⁺ ；¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.53 (s, 1H), 8.47 (s, 2H), 7.82 (s, 1H), 5.90 – 5.79 (m, 1H), 4.65 – 4.45 (m, 2H), 4.20 – 4.00 (m, 3H), 3.90 – 3.78 (m, 1H), 3.62 – 3.48 (m, 1H), 3.30 – 2.90 (m, 4H), 2.30 – 2.11 (m, 1H), 1.79 – 1.51 (m, 5H), 1.15 (d,J = 6.5 Hz, 3H)。 Example 12: 4-Bromo -5 - (((2S) -1 - ((2- oxo-l- (l- (5- (trifluoromethyl) pyrazol 𠯤-2-yl) piperidine - 4- yl) pyrrolidin-3-yl) oxy) propan-2-yl) amino) despair 𠯤 -3 (2H) - one synthesis of

Add 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl) at 100℃ Pyrrolidin-2-one hydrochloride (90 mg, 0.212 mmol, 1.00 equiv; see Example 13, step C), 4,5-dibromodazane-3(2H)-one (54 mg, 0.213 mmol, 1.00 Equiv) and Et ₃ N (65 mg, 0.637 mmol, 3.00 equiv) in n-butyl alcohol (2 mL) were stirred for 3 days. The resulting solution was concentrated and _{purified by reverse phase chromatography eluted with H 2} O/CH ₃ CN (53/47) to obtain impure desired product. The product was further purified by prep-HPLC to obtain 11 mg (9% yield) of 4-bromo-5-(((2S)-1-((2-oxo-1-(1- (5-(Trifluoromethyl)pyridin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)pyridine-3(2H) -ketone. LCMS (ESI, m/z): 560.10 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.53 (s, 1H), 8.47 (s, 2H), 7.82 (s, 1H) , 5.90 – 5.79 (m, 1H), 4.65 – 4.45 (m, 2H), 4.20 – 4.00 (m, 3H), 3.90 – 3.78 (m, 1H), 3.62 – 3.48 (m, 1H), 3.30 – 2.90 ( m, 4H), 2.30 – 2.11 (m, 1H), 1.79 – 1.51 (m, 5H), 1.15 (d, J = 6.5 Hz, 3H).

Example 13: 5 - (((S ) -1 - (((S) -2- oxo-1- (1- (5- (trifluoromethyl) pyrazol 𠯤-2-yl) piperidine - 4- yl) pyrrolidin-3-yl) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one (13A) and 5 - ((( S) -1 - (((R ) -2- oxo-1- (1- (5- (trifluoromethyl) pyrazol 𠯤-2-yl) -piperidin-4-yl) pyrrolidine -3 - yl) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one (13B)

In Step A , 3-hydroxy-1-(hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (717 mg, 3.26 mmol, 1.0 equiv; Intermediate I-3), 2- A solution of chloro-5-(trifluoromethyl)pyridine (654 mg, 3.58 mmol, 1.1 equiv) and K ₂ CO ₃ (900 mg, 6.51 mmol, 2.0 equiv) in DMF (8 mL) was stirred for 2 hours. Water was added and the resulting solution was extracted with 3×10 mL ethyl acetate. The organic layer was washed with 3×50 mL brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was applied to a silica gel column and eluted with dichloromethane/methanol (97:3) to obtain 702 mg (65% yield) of 3-hydroxy-1-(1-(5- (Trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one. LCMS (ES, m/z ): 331.15 [M+H] ⁺ .

Step B at 0 ℃ to methyl 3-hydroxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one (680 mg, 2.06 mmol, 1.0 equiv) Add NaH (60% dispersion in oil, 82 mg, 2.06 mmol, 1.0 equiv) to a solution in DMF (6 mL). The resulting solution was stirred at this temperature for 15 minutes and then (S)-4-methyl-1,2,3-oxathiazolidine-3-acetic acid tert-butyl 2,2-dioxide was added to the resulting solution (537 mg, 2.27 mmol, 1.1 equiv). After stirring for 2 hours at 0°C, 5 mL of water was added and the mixture was concentrated under vacuum. The residue was applied to a silica gel column eluted with ethyl acetate/petroleum ether (39:61) to obtain 500 mg (50% yield) of ((2S)-1-((2- Pendant oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amine Tertiary Butyl Carboxylate. LCMS (ES, m/z ): 488.25 [M+H] ⁺ .

Step C: ((2S)-1-((2-Pendoxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidine- A solution of 3-yl)oxy)prop-2-yl)carbamic acid tert-butyl ester (300 mg, 0.62 mmol, 1.0 equiv) in 4N HCl (5 mL) in dioxane was stirred at room temperature 1 hour and then concentrated under vacuum to obtain 200 mg (84% yield) of 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoro) as a yellow solid (Methyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride. LCMS (ES, m/z ): 388.20 [M+H] ⁺ .

Step D combines 3-((S)-2-aminopropoxy)-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidine -2-one hydrochloride (150 mg, 0.39 mmol, 1.0 equiv), triethylamine (78 mg, 0.77 mmol, 2.0 equiv) and 5-chloro-2-(4-methoxybenzyl)-4- A solution of (trifluoromethyl)pado-3(2H)-one (136 mg, 0.43 mmol, 1.1 equiv; Intermediate I-1) in EtOH (5.00 mL) was stirred at 60°C for 1 hour. The resulting mixture was concentrated and applied to a silica gel column eluted with ethyl acetate/petroleum ether (85:15) to obtain 160 mg (62% yield) of 2-(4-methoxybenzyl) as a white solid )-5-(((2S)-1-((2-side oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrole (Pyridin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one. (ES, m/z ): 670.20 [M+H] ⁺ .

Step E The 2-(4-methoxybenzyl)-5-(((2S)-1-((2-side oxy-1-(1-(5-(trifluoromethyl) (Yl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridine-3( A solution of 2H)-ketone (150 mg, 0.22 mmol, 1.0 equiv) in TFA (3.00 mL) was treated with trifluoromethanesulfonic acid (0.3 mL) and stirred at -10°C for 1 hour. 5 mL of ice water was added and the pH was adjusted to 8 _{with saturated aqueous Na 2} CO _{3 solution.} The resulting solution was extracted with 3×10 mL ethyl acetate and the organics were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase chromatography to obtain a mixture of isomers. By chiral prep-HPLC: (CHIRALPAK IG, 2.0*25cm, 5um; mobile phase A: Hex:DCM=3:1 w/10 mM NH ₃ -MeOH, mobile phase B: EtOH; flow rate: 16 mL/min ; 50% B for 19 min; 220/254 nm) further purify the mixture to obtain the desired isomer. The relative stereochemistry of the compound is assigned by analogy to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure.

Example 13 Isomer A (13A) : white solid 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyridine) 𠯤-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)da𠯤-3(2H)- Ketone (23 mg, 27% yield). LCMS (ESI, m/z): 550.20 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.45 (s, 1H), 8.47 (d, J = 3.1 Hz, 2H), 7.92 (s, 1H), 6.45 – 6.32 (m, 1H), 4.59 (d, J = 13.6 Hz, 2H), 4.18 -4.07 (m,3H), 3.84 (dd, J = 10.0, 4.2 Hz, 1H), 3.60 (dd, J = 10.0, 6.9 Hz, 1H), 3.25 – 3.19 (m, 1H), 3.18-3.04 (m, 3H), 2.25 – 2.17 (m, 1H), 1.80 – 1.55 (m, 5H), 1.18 (d, J = 6.0 Hz, 3H). Chiral HPLC: (CHIRALPAK IG-3, 4.6*50mm, 3 um; Hex:DCM=3:1 w/0.1%DEA: EtOH=80: 20; 1.0 mL/min, tR = 2.423 min.)

Example 13 Isomer B (13B) : white solid 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyridine) 𠯤-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)da𠯤-3(2H)- Ketone (45 mg, 53% yield). LCMS (ESI, m/z): 550.20 [M+H] ⁺ ; 1H NMR (300 MHz, DMSO-d ₆ ) δ 12.48 (s, 1H), 8.47 (d, J = 3.9 Hz, 2H), 7.95 ( s, 1H), 6.46 – 6.32 (m, 1H), 4.59 (d, J = 13.4 Hz, 2H), 4.18 -4.07 (m,3H), 3.83 (dd, J = 10.0, 6.6 Hz, 1H), 3.60 (dd, J = 10.0, 6.9 Hz, 1H), 3.25 – 3.19 (m, 1H), 3.16 – 2.99 (m, 3H), 2.25 – 2.17 (m, 1H), 1.81 – 1.56 (m, 5H), 1.17 (d, J = 6.4 Hz, 3H). Chiral HPLC: (CHIRALPAK IG-3, 4.6*50mm, 3 um; Hex:DCM=3:1 w/0.1%DEA: EtOH=80: 20; 1.0 mL/min, tR = 3.085 min.)

Example 14 : 6-(4-((S)-2 -oxo -3-((S)-2-((6 -oxo -5-( trifluoromethyl )-1,6- di hydrogen despair 𠯤 4-yl) amino) propoxy) pyrrolidin-l-yl) -piperidine-1-yl) nicotinic carbonitrile (14A) and 6- (4 - ((R) -2- Pendant oxy -3-((S)-2-((6 -Pendant oxy -5-( trifluoromethyl )-1,6- dihydrota- 4 -yl ) amino ) propoxy ) Synthesis of pyrrolidin- 1 -yl ) hexahydropyridin- 1 -yl ) nicotinonitrile ( 14B)

In step A, 3-hydroxy-1-(hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (700 mg, 3.17 mmol, 1.0 equiv; intermediate I-3), 6-chloronicotine methyl A solution of nitrile (440 mg, 3.18 mmol, 1.0 equiv) and K ₂ CO ₃ (1.30 g, 9.41 mmol, 2.97 equiv) in DMF (5 mL) was stirred at 50°C for 2 hours. The resulting solution was diluted with 10 mL of water. The solid was collected by filtration to obtain 530 mg (58% yield) of 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl) as a brown solid Nicotine carbonitrile. LCMS (ESI, m/z): 287.20 [M+H] ⁺ .

Step B Add 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotine carbonitrile (286 mg, 0.99 mmol, 1.0 equiv at 0°C) ) NaH (60% suspension in mineral oil, 133 mg, 3.33 mmol, 3.3 equiv) was added to the solution in DMF (5 mL) and the solution was stirred for 15 minutes. Add (S)-4-methyl-1,2,3-oxathiazolidine-3-acetic acid tert-butyl 2,2-dioxide (261 mg, 1.10 mmol, 1.10 equiv) and add the solution to 0 Stir at °C for 2 hours. Water was added and the resulting mixture was concentrated under vacuum. The crude product was purified by reversed phase chromatography eluted with H ₂ O/CH ₃ CN (40/60) to obtain 200 mg (45% yield) of ((2S)-1-((1 -(1-(5-Cyanopyridin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)aminocarboxylic acid Butyl ester. LCMS (ESI, m/z): 444.30 [M+H] ⁺ .

Step C ((2S)-1-((1-(1-(5-cyanopyridin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy A solution of tert-butyl propan-2-yl)carbamate (180 mg, 1.0 equiv) in 4N HCl (5 mL) in dioxane was stirred at room temperature for 2 hours. The resulting mixture was concentrated under vacuum to obtain 120 mg (78% yield) of 6-(4-(3-((S)-2-aminopropoxy)-2-oxopyrrolidine- as a white solid) 1-yl)hexahydropyridin-1-yl)nicotine carbonitrile hydrochloride. LCMS (ESI, m/z): 344.15 [M+H] ⁺ .

Step D is 6-(4-(3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile salt Acid acid salt (110 mg, 0.32 mmol, 1.0 equiv), 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl) 𠯤-3(2H)-one (101 mg, A solution of 0.32 mmol, 1.0 equiv; Intermediate I-1) and N-methylmorpholine (97 mg, 0.96 mmol, 3.0 equiv) in MeCN (2 mL) was stirred at 60°C for 12 hours. The mixture was concentrated under vacuum and the residue was applied to a silica gel column eluted with ethyl acetate/petroleum ether (9/1) to obtain 70 mg (23% yield) of white solid 6-(4- (3-((S)-2-((1-(4-Methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4- (Yl)amino)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotine carbonitrile. LCMS (ESI, m/z): 626.25 [M+H] ⁺ .

Step E Add 6-(4-(3-((S)-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl) -1,6-Dihydropyridin-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotine carbonitrile (40 mg, A solution of 0.064 mmol, 1.0 equiv) in TFA (3 mL) was treated with trifluoromethanesulfonic acid (0.3 mL) and stirred at this temperature for 1 hour. Add 10 mL of ice water and adjust the pH of the solution to 5-6 _{with saturated Na 2} CO _{3 aqueous solution.} The resulting solution was extracted with 3 × 10 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by reversed phase chromatography eluted with H ₂ O/CH ₃ CN (60/40) to obtain a mixture of isomers. The product was further purified by chiral prep HPLC with the following conditions: (CHIRALPAK IA, 2*25cm, 5um; mobile phase A: Hex:EtOH=1:1 w/8 mmol/L NH ₃ -MeOH, mobile phase B: EtOH; flow rate: 16 mL/min; 50% B: for 18 min; 220/254 nm) to obtain separated isomers. The relative stereochemistry of the compound is assigned by analogy to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure.

Example 14 Isomer A (14A) : white solid 6-(4-((S)-2-oxo-3-((S)-2-((6-oxo-5-(three) (Fluoromethyl)-1,6-Dihydropyridine-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (11 mg, 33%) Yield). LCMS (ESI, m/z): 506.20 [M+H] ⁺ ; ¹ H-NMR (methanol- d ₄ , 400 MHz) δ 8.40 (s, 1H), 7.98 (s, 1H), 7.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.90 (dd, J = 9.2, 0.8 Hz, 1H), 4.64 (m, J = 13.5 Hz, 2H), 4.19- 4.10 (m, 3H), 3.99 (dd, J = 9.8, 3.8 Hz, 1H), 3.63 (dd, J = 9.8, 6.8 Hz, 1H), 3.38 (dd, J = 9.7, 3.6 Hz, 1H), 3.29 – 3.21 (m, 2H), 3.10 – 2.98 (m , 2H), 2.42 – 2.29 (m, 1H), 2.42 – 2.29 (m, 1H), 1.92 – 1.79 (m, 1H), 1.78 – 1.65 (m, 4H), 1.30 (d, J = 6.6 Hz, 3H ). Chiral HPLC: (CHIRALPAK IA-3, 4.6*50mm, 3um; Hex w/ 0.1%DEA: EtOH = 50:50; flow rate: 1 mL/min; tR = 2.167 min).

Example 14 Isomer B (14B) : white solid 6-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(tri (Fluoromethyl)-1,6-Dihydropyridine-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (14 mg, 43%) Yield). LCMS (ESI, m/z): 506.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.40 (dd, J = 2.4, 0.7 Hz, 1H), 8.00 (s, 1H) , 7.72 (dd, J = 9.1, 2.4 Hz, 1H), 6.90 (dd, J = 9.2, 0.8 Hz, 1H), 4.64 (m, J = 13.5 Hz, 2H), 4.19- 4.10 (m, 3H), 3.99 (dd, J = 9.8, 3.8 Hz, 1H), 3.63 (dd, J = 9.8, 6.8 Hz, 1H), 3.38 (dd, J = 9.7, 3.6 Hz, 1H), 3.29 – 3.21 (m, 2H) , 3.10 – 2.98 (m, 2H), 2.42 – 2.29 (m, 1H), 1.92 – 1.79 (m, 1H), 1.78 – 1.65 (m, 4H), 1.30 (d, J = 6.6 Hz, 3H). Chiral HPLC: (CHIRALPAK IA-3, 4.6*50mm, 3um; Hex w/ 0.1%DEA: EtOH = 50:50; flow rate: 1 mL/min; tR = 3.159 min).

Example 15 : 5-(((S)-1-(((S)-1-(1-(5-( Difluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl )-2- oxo pyrrolidin-3-yl) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one (15A) and 5 - (((S )-1-(((R)-1-(1-(5-( Difluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl )-2 -oxopyrrolidin- 3 -yl ) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one synthesis of (15B) of

In step A, 3-hydroxy-1-(hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (1.20 g, 5.437 mmol, 1.99 equiv; intermediate I-3), 2-chloro-5- A solution of (difluoromethyl)pyrimidine (450 mg, 2.735 mmol, 1.00 equiv) and K ₂ CO ₃ (2.27 g, 16.43 mmol, 6.01 equiv) in DMF (15 mL) was stirred at 80°C for 15 hours. After filtration, the filtrate was concentrated under vacuum and the crude product was applied to a _{reverse phase column eluted with H 2} O/CH ₃ CN (1:1) to obtain 450 mg (46% yield) of a yellow solid 1-(1-(5-(Difluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one. LCMS (ESI, m/z): 313.20 [M+H] ⁺ .

Step B Add 1-(1-(5-(difluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one (150 mg, 0.480 mmol, 1.00 equiv) NaH (120 mg, 3.00 mmol, 6.25 equiv, 60% dispersion in mineral oil) was added to the solution in DMF (10 mL) and stirred for 10 min. Add (S)-4-methyl-1,2,3-oxathiazolidine-3-acetic acid tert-butyl 2,2-dioxide (177 mg, 0.746 mmol, 1.55) to the solution at 0°C equiv). The resulting solution was stirred at room temperature for 2 hours. The reaction was then quenched by adding 0.2 mL of 20% sodium carbonate aqueous solution. The solution was concentrated and the crude product was applied to a _{reversed-phase column eluted with H 2} O/CH ₃ OH (40/60) to obtain 224 mg (50% yield) of an orange solid ((2S)-1 -((1-(1-(5-(Difluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2 -Base) tertiary butyl carbamate. LCMS (ESI, m/z): 470.15 [M+H] ⁺ .

Step C ((2S)-1-((1-(1-(5-(Difluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -Yl)oxy)prop-2-yl)carbamate (250 mg, 0.532 mmol, 1.00 equiv) in 4N HCl (5 mL) in dioxane, stir at room temperature 2 Hour. The resulting mixture was concentrated to obtain 220 mg (71% yield) of 3-((S)-2-aminopropoxy)-1-(1-(5-(difluoromethyl)pyrimidine-) as an orange solid 2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride. LCMS (ESI, m/z): 370.15 [M+H] ⁺ .

Step D combines 3-[(2S)-2-aminopropoxy]-1-[1-[5-(difluoromethyl)pyrimidin-2-yl]hexahydropyridin-4-yl]pyrrolidine- 2-ketone hydrochloride (220 mg, 0.542 mmol, 1.00 equiv), 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl) 𠯤-3- A solution of ketone (189 mg, 0.593 mmol, 1.09 equiv) and TEA (180 mg, 1.779 mmol, 3.28 equiv) in EtOH (5 mL) was stirred at 60°C for 3 hours. The mixture was concentrated and diluted with 100 mL ethyl acetate and washed with 2×20 mL saturated aqueous ammonium chloride solution. The aqueous layers were combined and extracted with 2×50 mL ethyl acetate. The organics were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column eluted with 100% ethyl acetate to obtain 107 mg (30% yield) of 5-(((2S)-1-((1-(1- (5-(Difluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)amino)-2 -(4-Methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one. LCMS (ESI, m/z): 652.50 [M+H] ⁺ .

Step E The 5-(((2S)-1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrole (Pyridin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one (100 A solution of mg, 0.153 mmol, 1.00 equiv) in trifluoromethanesulfonic acid/TFA = 1:10 (1.5 mL) was stirred at room temperature for 2 hours. Dilute the resulting solution with 1.5 mL H _{2 O.} Adjust the pH value of the solution to 7-8 with 20% sodium carbonate aqueous solution. The resulting solution was extracted with 2 × 20 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by reverse phase chromatography eluted with H ₂ O/CH _{3 CN.} By chiral prep-HPLC (CHIRAL ART Cellulose -SB, 2*25cm, 5um; mobile phase A: Hex w/ 8mmol/L NH ₃ -MeOH, mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 50% B for 16 min; 220/254 nm) to further purify the product. The relative stereochemistry of the compound is assigned by analogy to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure.

Example 15 Isomer A (15A) : 5-(((S)-1-(((S)-1-(1-(5-(Difluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one (16 mg , 32% yield, off-white solid). LCMS (ESI, m/z): 532.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.44 (s, 1H), 8.54 (s , 2H), 7.91 (s, 1H), 6.96 (t, J = 55.5 Hz, 1H), 6.41 – 6.32 (m, 1H), 4.86 – 4.75 (m, 2H), 4.21 – 4.14 (m, 1H), 4.08 – 4.04 (m, 2H), 3.83 (dd, J = 10.0, 4.3 Hz, 1H), 3.59 (dd, J = 10.1, 7.0 Hz, 1H), 3.25 – 3.19 (m, 1H), 3.15 – 3.08 ( m, 1H), 3.02 – 2.95 (m, 2H), 2.25 – 2.16 (m, 1H), 1.73 – 1.48 (m, 5H), 1.16 (d, J = 6.5 Hz, 3H). Chiral HPLC: CHIRAL Cellulose-SB, 0.46*10cm, 3um; Hex w/0.1% DEA: EtOH = 50:50; Flow rate: 1.0 mL/min; rT = 2.642 min.

Example 15 Isomer B (15B) : 5-(((S)-1-(((R)-1-(1-(5-(difluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one (25 mg , 50% yield, off-white solid). LCMS (ESI, m/z): 532.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.46 (s, 1H), 8.54 (s , 2H), 7.94 (s, 1H), 6.96 (t, J = 55.5 Hz, 1H), 6.41 – 6.32 (m, 1H), 4.86 – 4.75 (m, 2H), 4.21 – 4.14 (m, 1H), 4.08 – 4.03 (m, 2H), 3.83 (dd, J = 10.0, 4.3 Hz, 1H), 3.59 (dd, J = 10.1, 7.0 Hz, 1H), 3.25 – 3.20 (m, 1H), 3.15 – 3.09 ( m, 1H), 3.03 – 2.95 (m, 2H), 2.25 – 2.17 (m, 1H), 1.73 – 1.66 (m, 1H), 1.61 – 1.48 (m, 4H), 1.17 (d, J = 6.5 Hz, 3H). Chiral HPLC: Chiral Cellulose-SB, 0.46*10cm, 3um; Hex w/0.1% DEA: EtOH = 50:50; Flow rate: 1.0 mL/min; rT = 4.415 min.

Example 16 : 5-(((S)-1-(((R)-1-(1-(5- chloropyrimidin -2- yl ) hexahydropyridin- 4 -yl )-2 -oxopyrrolidine 3- yl) oxy) propan-2-yl) amino) (trifluoromethyl) despair 𠯤 -3 (2H) -4- - one synthesis of

In step A, (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)acetaldehyde (3.47 g, 21.941 mmol, 1.00 equiv), A solution of 4-aminohexahydropyridine-1-acetate (6.40 g, 31.955 mmol, 1.46 equiv) and acetic acid (2.64 g, 43.962 mmol, 2.00 equiv) in DCM (200 mL) was stirred for 15 minutes. NaBH(AcO) ₃ (14.00 g, 66.042 mmol, 3.01 equiv) was added and the solution was stirred at room temperature for another 2 hours. Add 300 mL of saturated aqueous NaHCO ₃ solution. The layers were separated, and the aqueous layer was extracted with 3×200 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (75/25) to obtain 2.9 g (46% yield) of (R)-4-(3-hydroxy- 2-Pyrridine-1-yl)hexahydropyridine-1-acetate tert-butyl ester. LCMS (ESI, m/z): 285.15 [M+H] ⁺ .

Step B: Put (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetate (2.90 g, 10.2 mmol, 1.00 equiv) in 1, The solution in 4-dioxane (10 mL) and 4N HCl (30 mL) in dioxane was stirred at room temperature for 15 hours. The solution was concentrated to obtain 2.2 g (98% yield) of (R)-3-hydroxy-1-(hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride as a yellow solid. LCMS (ESI, m/z): 185.15 [M+H] ⁺ .

Step C: Combine (R)-3-hydroxy-1-(hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (700 mg, 3.172 mmol, 1.00 equiv), K ₂ CO ₃ (1310 mg, A solution of 9.479 mmol, 2.99 equiv) and 2,5-dichloropyrimidine (492 mg, 3.303 mmol, 1.04 equiv) in DMF (5 mL) was stirred at 80°C for 4 hours. 25 mL water was added and the resulting solution was extracted with 3 x 20 mL dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was applied to a silica gel column eluted with dichloromethane/MeOH (10:1) to obtain 750 mg (80% yield) of light yellow solid (R)-1-(1-(5 -Chloropyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one. LCMS (ESI, m/z): 297.05 [M+H] ⁺ .

Step D: Add (R)-1-(1-(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one (350 mg, 1.179 mmol) at 0°C , 1.00 equiv) Add NaH (60% dispersion in mineral oil, 236 mg, 5.901 mmol, 5 equiv) to the solution in DMF (6 mL). (S)-4-Methyl-1,2,3-oxathiazolidine-3-acetic acid tert-butyl 2,2-dioxide (420 mg, 1.770 mmol, 1.50 equiv) was added to the solution. The resulting solution was warmed to room temperature. 0.5 mL of water was added and the solvent was removed in vacuum. The crude product was purified by reverse phase chromatography eluted with H ₂ O/CH ₃ OH (7/3) to obtain 490 mg (82% yield) of ((S)-1-(() (R)-1-(1-(5-Chloropyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)amine Tertiary Butyl Carboxylate. LCMS (ESI, m/z): 454.15 [M+H] ⁺ .

Step E will ((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3- (Yl)oxy)prop-2-yl)carbamate (490 mg, 1.079 mmol, 1.00 equiv) in 1,4-dioxane (10.00 mL) and dioxane in 4N HCl (5.00 The solution in mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated to obtain 420 mg (90% yield) of (R)-3-((S)-2-aminopropoxy)-1-(1-(5-chloropyrimidine-) as a pale yellow solid 2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride. LCMS (ESI, m/z): 354.15 [M+H] ⁺ .

Step F (R)-3-((S)-2-aminopropoxy)-1-(1-(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine-2 -Ketone hydrochloride (210 mg, 0.538 mmol, 1.00 equiv), TEA (190 mg, 1.878 mmol, 3.49 equiv) and 5-chloro-2-[(4-methoxyphenyl)methyl]-4- A solution of (trifluoromethyl)pada-3-one (205 mg, 0.643 mmol, 1.20 equiv) in EtOH (5 mL) was stirred at 50°C for 4 hours. The mixture was concentrated, diluted with 60 mL of ethyl acetate, and washed with 2×20 mL of saturated _{aqueous NH 4} Cl. The layers were separated and the aqueous layer was extracted with 2×50 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate/petroleum ether (3/1) to obtain 240 mg (70% yield) of white solid 5-(((S)-1-() ((R)-1-(1-(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl) Amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one. LCMS (ESI, m/z): 652.50 [M+H] ⁺ .

Step G Add 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl)-2-side at room temperature (Oxypyrrolidin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pha 𠯤-3(2H)- A solution of ketone (230 mg, 0.362 mmol, 1.00 equiv) in trifluoromethanesulfonic acid/TFA=1:10 (2.50 mL) was stirred for 2 hours. Add 15 mL of water and adjust the pH of the solution to 7-8 with a 20% aqueous sodium bicarbonate solution. The solution was extracted with 3 × 20 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by reverse phase chromatography with H ₂ O/CH ₃ CN elution to obtain 99 mg 5-(((S)-1-(((R)-1-(1-(5-chloro (Pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl) -3(2H)-ketone. LCMS (ESI, m/z): 516.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.47 (s, 1H), 8.42 (s, 2H), 7.95 (s, 1H) , 6.36 – 6.33 (m, 1H), 4.70 – 4.67 (m, 2H), 4.18 – 4.02 (m, 3H), 3.83 (dd, J = 10.0, 6.6 Hz, 1H), 3.61 (dd, J = 10.0, 4.7 Hz, 1H), 3.34 – 3.21 (m, 1H), 3.14 – 3.11 (m, 1H), 2.98 – 2.92 (m, 2H), 2.25 – 2.23 (m, 1H), 1.74 – 1.69 (m, 1H) , 1.60 – 1.51 (m, 4H), 1.17 (d, J = 6.5 Hz, 3H).

Example 17 : 6-(4-((S)-3-((S)-3 -methoxy- 2-((6- side oxy -5-( trifluoromethyl )-1,6- di hydrogen despair 𠯤 4-yl) amino) propoxy) -2-oxo pyrrolidin-1-yl) -piperidine-1-yl) nicotinic carbonitrile (. 17A) and 6- (4- ( (R)-3-((S)-3 -Methoxy- 2-((6 -Pendant oxy -5-( trifluoromethyl )-1,6- dihydrota- 4 -yl ) amine yl) propoxy) -2-oxo pyrrolidin-1-yl) -piperidine-1-yl) nicotinic-carbonitrile (17B) synthesis of

Step A Add 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotine carbonitrile (300 mg, 1.048 mmol, 1.00 equiv Example 14, Step A) NaH (126 mg, 5.239 mmol, 5 equiv) was added to the solution in DMF (5 mL). The solution was stirred at 0°C for 10 min and then (S)-4-(methoxymethyl)-1,2,3-oxathiazolidine-3-acetic acid tert-butyl ester 2,2-dioxide was added (336 mg, 1.26 mmol, 1.2 equiv). The solution was stirred for another hour at 0°C. 20 mL of methanol was added and the solution was concentrated. The crude product was purified by C18 reverse phase chromatography eluted with water/ACN (30/70) to obtain 121 mg (24% yield) of ((2S)-1-((1-(1- (5-cyanopyridin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)-3-methoxyprop-2-yl)aminocarboxylic acid Tertiary butyl ester. LCMS (ESI, m/z): 474.25 [M+H] ⁺ .

Step B ((2S)-1-((1-(1-(5-cyanopyridin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy (Yl)-3-methoxyprop-2-yl)carbamic acid tert-butyl ester (121 mg, 0.256 mmol, 1.00 equiv) in 4N HCl (8 mL) in dioxane at room temperature Stir for 1.5 hours. The mixture was concentrated under vacuum to obtain 89 mg (93% yield) of 6-(4-(3-((S)-2-amino-3-methoxypropoxy)-2- Pendant pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotine carbonitrile hydrochloride. LCMS (ESI, m/z): 374.10 [M+H] ⁺ .

In step C, 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)- 3(2H)-one (61 mg, 0.191 mmol, 1.00 equiv; Intermediate I- 1), 6-(4-(3-((S)-2-amino-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl ) A solution of nicotine carbonitrile hydrochloride (71 mg, 0.191 mmol, 1.0 equiv) and TEA (58 mg, 0.574 mmol, 3.0 equiv) in ethanol (4.00 mL) was stirred in an oil bath at 70°C for 4 hours . The mixture was concentrated under vacuum and the crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (10:1) to obtain 60 mg (48% yield) of a yellow oily 6-(4- (3-((S)-3-methoxy-2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-di (Hydroxypyridin-1-yl) hexahydropyridin-1-yl) nicotine carbonitrile. LCMS (ESI, m/z): 656.20 [M+H] ⁺ .

Step D Add 6-(4-(3-((S)-3-methoxy-2-((1-(4-methoxybenzyl)-6-pendant oxy-5- (Trifluoromethyl)-1,6-dihydropyridine-1-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotine A solution of formonitrile (54 mg, 0.082 mmol, 1.00 equiv) in TFA (2 mL) was treated with trifluoromethanesulfonic acid (0.2 mL) and stirred at the same temperature for 30 min. Add 10 mL of ice water and adjust the pH of the solution to 8 with a 40% aqueous sodium hydroxide solution. The resulting solution was extracted with 3 × 20 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by reverse phase chromatography eluted with water/ACN (60/40) to obtain a mixture of isomers. The diastereomers were separated by chiral prep-HPLC with the following conditions: CHIRALPAK IF, 2*25cm, 5um; mobile phase A: Hex w/ 8mM NH ₃ -MeOH, mobile phase B: EtOH; flow rate: 20 mL /min; gradient: 50% B for 22 min; 220/254 nm. ) The relative stereochemistry of the compound is assigned by similar to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure.

Example 17 Isomer A (17A) : 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl) )-1,6-Dihydropyridine-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (5.3 mg , 12% yield, white solid). LCMS (ESI, m/z): 536.20[M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.48 (s, 1H), 8.47 (s , 1H), 7.93 (s, 1H), 7.83 (d, J = 9.1Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 6.33 – 6.28 (m, 1H), 4.58 –4.50 (m, 2H), 4.33 – 4.26 (m, 1H), 4.09 – 4.01 (m, 2H), 3.92 – 3.87 (m, 1H), 3.69 – 3.63 (m, 1H), 3.48 (d, J = 5.7 Hz, 2H) , 3.28 – 3.27 (m, 3H), 3.23 – 3.19 (m, 1H), 3.15 – 3.08 (m, 1H), 3.03 – 2.95 (m, 2H), 2.27 – 2.19 (m, 1H), 1.73 – 1.48 ( m, 5H). Chiral HPLC: CHIRALPAK IF-3, 4.6*50mm, 3 µm; Hex w/ 0.1% DEA: EtOH = 50:50; Flow rate: 1 mL/min; rT = 2.405 min.

Example 17 Isomer B (17B) : 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl) )-1,6-Dihydropyridine-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (9 mg , 20% yield, white solid). LCMS (ESI, m/z): 536.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.50 (s, 1H), 8.47 (s , 1H), 7.96 (s, 1H), 7.83 (d, J = 9.1 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.33 – 6.28 (m, 1H), 4.58-4.50 (m, 2H), 4.33-4.26 (m, 1H), 4.11 – 4.01 (m, 2H), 3.92-3.87 (m, 1H), 3.69-3.63 (m, 1H), 3.49 (d, J = 5.3 Hz, 2H) , 3.29-3.26 (m, 3H), 3.23-3.19 (m, 1H), 3.15-3.08(m,1H), 3.03-2.94(m, 2H), 2.27-2.18 (m, 1H), 1.73 -1.48 ( m, 5H). Chiral HPLC: CHIRALPAK IF-3, 4.6*50mm, 3 µm; Hex w/ 0.1% DEA: EtOH = 50:50; Flow rate: 1 mL/min; rT = 3.678 min.

5-(((S)-1-甲氧基-3-(((S)-2-側氧基-1-(1-(5-(三氟甲基)吡𠯤-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 580.20 [M+H]⁺ ；¹ H NMR (400 MHz, DMSO-d₆ ) δ 12.48 (s, 1H), 8.46 (d,J = 4.2 Hz, 2H), 7.93 (s, 1H), 6.41-6.29 (m, 1H), 4.62-4.55 (m, 2H), 4.34-4.27 (m, 1H), 4.11-4.03 (m, 2H), 3.90 (dd,J = 10.2, 4.7 Hz, 1H), 3.66 (dd,J = 10.2, 6.5 Hz, 1H), 3.48 (d,J = 5.5 Hz, 2H), 3.31-3.30(m, 3H), 3.28-3.21 (m, 2H), 3.09-3.04 (m, 2H), 2.29 – 2.17 (m, 1H), 1.75 – 1.54 (m, 5H)；手性HPLC：CHIRALPAK IF-3, 4.6*50mm, 3µm；Hex w/ 0.1%DEA : EtOH = 50:50；流速： 1 mL/min；rT = 1.858 min。 18B   

5-(((S)-1-甲氧基-3-(((R)-2-側氧基-1-(1-(5-(三氟甲基)吡𠯤-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 580.20 [M+H]⁺ ；¹ H NMR (400 MHz, DMSO-d₆ ) δ 12.50 (s, 1H), 8.49 – 8.43 (d, J = 4.0 Hz, 2H), 7.96 (s, 1H), 6.31-6.23 (m, 1H), 4.61-4.54 (m, 2H), 4.33-4.28 (m, 1H), 4.14-4.03 (m, 2H), 3.90 (dd,J = 10.2, 4.7 Hz, 1H), 3.66 (dd,J = 10.2, 6.5 Hz, 1H), 3.49 (d, J = 5.3 Hz, 2H), 3.28-3.27 (m, 3H),3.26-3.21 (m, 2H), 3.15-3.02 (m, 2H), 2.25-2.18 (m, 1H), 1.78-1.56 (m, 5H)；手性HPLC：CHIRALPAK IF-3, 4.6*50mm, 3µm；Hex w/ 0.1%DEA : EtOH = 50:50；流速： 1 mL/min；rT = 2.577 min。 Example 18 is based on 6-(4-((S)-3-((S)-3-methoxy-2-((6- pendant oxy-5-(trifluoromethyl)-1,6 -Dihydropyridine-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile and 6-(4-(( R)-3-((S)-3-methoxy-2-((6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)amino group )Propoxy)-2-Pyridin-1-yl)hexahydropyridin-1-yl)nicotine carbonitrile (see Example 17) The procedure described in the synthesis, use appropriate building components and Synthesize by modifying reaction conditions (such as reagent ratio, temperature, coupling conditions, and reaction time). The relative stereochemistry of the compound is assigned by analogy to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure. Instance number structure analyze data 18A

5-(((S)-1-methoxy-3-(((S)-2-side oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexa (Hydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 580.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.48 (s, 1H), 8.46 (d, J = 4.2 Hz, 2H), 7.93 (s, 1H), 6.41-6.29 (m, 1H), 4.62-4.55 (m, 2H), 4.34-4.27 (m, 1H), 4.11-4.03 (m, 2H), 3.90 (dd, J = 10.2, 4.7 Hz, 1H), 3.66 (dd, J = 10.2, 6.5 Hz, 1H), 3.48 (d, J = 5.5 Hz, 2H), 3.31-3.30(m, 3H), 3.28-3.21 (m, 2H), 3.09-3.04 (m, 2H), 2.29 – 2.17 (m, 1H), 1.75 – 1.54 (m, 5H); Chiral HPLC: CHIRALPAK IF-3, 4.6*50mm, 3µm; Hex w/ 0.1%DEA: EtOH = 50:50; flow rate: 1 mL/min; rT = 1.858 min. 18B

5-(((S)-1-methoxy-3-(((R)-2-side oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexa (Hydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 580.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.50 (s, 1H), 8.49 – 8.43 (d, J = 4.0 Hz, 2H) , 7.96 (s, 1H), 6.31-6.23 (m, 1H), 4.61-4.54 (m, 2H), 4.33-4.28 (m, 1H), 4.14-4.03 (m, 2H), 3.90 (dd, J = 10.2, 4.7 Hz, 1H), 3.66 (dd, J = 10.2, 6.5 Hz, 1H), 3.49 (d, J = 5.3 Hz, 2H), 3.28-3.27 (m, 3H), 3.26-3.21 (m, 2H) ), 3.15-3.02 (m, 2H), 2.25-2.18 (m, 1H), 1.78-1.56 (m, 5H); Chiral HPLC: CHIRALPAK IF-3, 4.6*50mm, 3µm; Hex w/ 0.1%DEA : EtOH = 50:50; Flow rate: 1 mL/min; rT = 2.577 min.

Example 19 : 5-(((S)-1 -methoxy- 3-(((S)-2- pendant oxy- 1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl) ) hexahydro-4-yl) pyrrolidin-3-yl) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one (. 19A) and 5-(((S)-1 -methoxy- 3-(((R)-2 -oxo- 1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydro -one (19B) of - pyridin-4-yl) pyrrolidin-3-yl) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H)

Step A: Add 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one (500 mg, 1.51 mmol, 1.00 equiv) Add NaH (60% dispersion in mineral oil, 121 mg, 3.02 mmol, 2.0 equiv) to the solution in DMF (5 mL). After stirring at this temperature for 15 minutes, (S)-4-(methoxymethyl)-1,2,3-oxathiazolidine-3-acetic acid tert-butyl ester 2, A solution of 2-dioxide (605 mg 2.26 mmol, 1.50 equiv) in DMF (3 mL). The resulting solution was stirred at 0°C for 2 h. 50 mL water was added and the solution was extracted with 3×50 mL EtOAc. The organic layers were combined, washed with 50 mL brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was applied to a silica gel column eluted with EtOAc/petroleum ether (11:9) to obtain 500 mg (64% yield) of brown oil ((2S)-1-methoxy-3- ((2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2- Yl) tertiary butyl carbamate. LCMS (ESI, m/z): 518.20 [M+H] ⁺

Step B combines ((2S)-1-methoxy-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4- (Yl)pyrrolidin-3-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester (500 mg, 0.97 mmol, 1.00 equiv) in 1,4-dioxane in 4N HCl (4 mL The solution in) was stirred at room temperature for 1 h. After concentration, the _{crude product was purified by C18 reverse phase chromatography eluted with H 2} O/CH ₃ CN (1:1) to obtain 260 mg (65% yield) of 3-((S) as a yellow solid -2-amino-3-methoxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one . LCMS (ESI, m/z): 418.20 [M+H] ⁺ .

Step C The 3-((S)-2-amino-3-methoxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4 -Yl) pyrrolidin-2-one (250 mg, 0.60 mmol, 1.00 equiv), 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)pada-3(2H )-Ketone (286 mg, 0.90 mmol, 1.50 equiv; Intermediate I-1) and N-methylmorpholine (91 mg, 0.90 mmol, 1.50 equiv) in CH ₃ CN (4 mL) at 60℃ Stir for 1 h. The solution was diluted with 50 ml water and extracted with 3×50 mL EtOAc. The organic layers were combined, washed with 50 mL brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column eluted with EtOAc/petroleum ether (7:13) to obtain 100 mg (24% yield) of 5-(((2S)-1-methoxy) as a yellow solid -3-((2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propane -2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one. LCMS (ESI, m/z): 700.20[M+H] ⁺

Step D combines 5-(((2S)-1-methoxy-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine) -4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)da 𠯤-3( A solution of 2H)-ketone (90 mg, 0.13 mmol, 1.00 equiv) in TFA (1.00 mL) and trifluoromethanesulfonic acid (0.20 mL) was stirred at room temperature for 1 h. The residue was diluted with 20 ml water and the pH was adjusted to 7~8 _{with saturated aqueous Na 2} CO _{3 solution.} The resulting solution was extracted with 3 × 20 mL EtOAc. The organic layers were combined, washed with 20 mL brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by a C18 reverse phase column eluted with H ₂ O / CH _{3 CN (16:29).} By chiral prep-HPLC (CHIRALPAK IA, 2*25cm, 5um; mobile phase A: Hex (8mmol/L NH ₃ -MeOH), mobile phase B: EtOH; flow rate: 18 mL/min; 50% B for 20 min; 220/254 nm) to further purify the product. The relative stereochemistry of the compound is assigned by analogy to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure.

Example 19 Isomer A (19A) : 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl) Yl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H )-Ketone (20.8 mg, 28% yield, white solid). LCMS (ESI, m/z): 580.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.48 (s, 1H), 8.69 (s, 2H), 7.93 (s, 1H), 6.37-6.30 (m, 1H), 4.88-4.74 (m, 2H), 4.35-4.24 (m, 1H), 4.14 – 4.03 (m, 2H), 3.90 (dd, J=10.0 Hz, 3.6Hz, 1H), 3.70-3.61 (m, 1H), 3.51-3.44 (m, 2H), 3.29-3.25 (m, 3H), 3.23-3.17 (m , 1H), 3.17 – 2.97 (m, 3H), 2.26 – 2.18 (m, 1H), 1.78-1.49 (m, 5H); Chiral HPLC: CHIRALPAK IA-3, 4.6*50mm, 3μm; Hex: EtOH = 50:50; flow rate = 1.3 mL/min; rT = 1.33 min.

Example 19 Isomer B (19B) : 5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl) Yl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H )-Ketone (25.0 mg, 34% yield, white solid). LCMS (ESI, m/z): 580.20 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.49 (s, 1H), 8.69 (s, 2H), 7.96 (s, 1H), 6.32 – 6.24 (m, 1H), 4.86-4.77 (m, 2H) ), 4.35-4.24 (m, 1H), 4.15 – 4.00 (m, 2H), 3.90 (dd, J=10.0 Hz, 3.6 Hz, 1H), 3.71-3.63 (m, 1H), 3.52-3.45 (m, 2H), 3.28-3.27 (m, 3H) 3.24-3.21 (m, 1H), 3.18-2.97 (m, 3H), 2.31 – 2.19 (m, 1H), 1.77-1.49 (m, 5H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50mm, 3μm; Hex: EtOH = 50:50; Flow rate = 1.3 mL/min; rT = 2.91 min

Example 20 : 5-(((S)-1-(((S)-2 -oxo- 1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridine -4 - yl) pyrrolidin-3-yl) oxy) propan-2-yl) oxy) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one (20A) and 5 - (((S )-1-(((R)-2 -oxo- 1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl ) pyrrolidin- 3 -yl ) oxy) propan-2-yl) oxy) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one synthesis of (20B) of

Step A: 3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one (500 mg, 1.51 mmol, 1.00 equiv ), a solution of 4-toluenesulfonyl chloride (864 mg, 4.53 mmol, 2.99 equiv) and TEA (612 mg, 6.06 mmol, 4.00 equiv) in DCM (15 mL) was stirred at 25°C for 4 hours. The resulting solution was diluted with 50 mL of water. The layers were separated, and the aqueous layer was extracted with 3×50 mL dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain 500 mg (68% yield) of 4-toluenesulfonic acid 2-oxo-1-(1-(5- (Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl ester. LCMS (ESI, m/z): 485.20 [M+H] ⁺ .

Step B: (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (264 mg, 1.65 mmol, 2.00 equiv) in DMF (4 mL The solution in) was treated with NaH (60% dispersion in mineral oil, 67 mg, 1.65 mmol, 2.00 equiv) in DMF (4 mL) and stirred at this temperature for 15 minutes. Add 4-toluenesulfonic acid 2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl ester (400 mg , 0.83 mmol, 1.00 equiv) and the solution was stirred at room temperature for 2 hours. Add 20 mL of saturated _{aqueous NH 4} Cl and ethyl acetate. The layers were separated, and the aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, washed with 5 mL brine, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 450 mg of brown oily 3-((2S)-2-((tetrahydro-2H-pyran-2-yl )Oxy)propoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one, which is without further purification continue to use. LCMS (ESI, m/z): 473.0 [M+H] ⁺ .

Step C The 3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)-1-(1-(5-(trifluoromethyl)pyrimidine- A solution of 2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one (900 mg, 1.91mmol, 1.00 equiv) in 4N HCl (6 mL) in dioxane was stirred at room temperature for 1 hour . The resulting mixture was concentrated and the residue was applied to a _{reverse phase column eluted with H 2} O/CH ₃ CN (1:2) to obtain 250 mg (34% yield) of 3-((S )-2-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one. LCMS (ESI, m/z): 389.10 [M+H] ⁺ .

Step D combines 3-((S)-2-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine-2 -Ketone (75 mg, 0.16 mmol, 1.00 equiv), 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl) 𠯤-3(2H)-ketone (184 mg, A solution of 0.58 mmol, 3.64 equiv; Intermediate I-1) and potassium tert-butoxide (65 mg, 0.58 mmol, 3.65 equiv) in DCM (3.00 mL) was stirred at room temperature for 15 hours. The resulting solution was diluted with 50 mL DCM and washed with 50 ml H ₂ O and 50 mL brine. The mixture was dried over anhydrous sodium sulfate and concentrated. The crude product was applied to a silica gel column eluted with EtOAc/petroleum ether (7/3) to obtain 70 mg (66% yield) of colorless oily 2-(4-methoxybenzyl)-5 -(((2S)-1-((2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine-3- (Yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one. LCMS (ESI, m/z): 671.20 [M+H] ⁺ .

Step E The 2-(4-methoxybenzyl)-5-(((2S)-1-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine-2 -Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one (65 A solution of mg, 0.10 mmol, 1.00 equiv) in TFA (1 mL) and trifluoromethanesulfonic acid (0.20 mL) was stirred at room temperature for 1 hour. The solution was diluted with water and adjusted to pH 7~8 _{with saturated aqueous Na 2} CO _{3 solution.} After concentration, the crude product was purified by C18 reverse phase chromatography eluted _{with H 2} O/CH _{3 CN (52:48).} The product was further purified by chiral-Prep-HPLC with the following conditions: (CHIRALPAK IA, 2*25cm, 5 µm; mobile phase A: Hex w/8mM NH ₃ -MeOH, mobile phase B: EtOH; flow rate: 20 mL /min; 50% B for 15 min; 220/254 nm.) By similar to Example 10, based on the more active diastereomer PARP7 efficacy and similar to Example 10A X-ray crystal structure distribution of the relative compound Stereochemistry.

Example 20 Isomer A (20A) : 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine-2- (Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one (13 mg , 24% yield, white solid). LCMS (ESI, m/z): 551.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.22 (s, 1H), 8.69 (s , 2H), 8.28 (s, 1H), 5.22 – 5.12 (m, 1H), 4.86-4.76 (m, 2H), 4.11 – 3.94 (m, 3H), 3.65 – 3.58 (m, 1H), 3.24 – 3.16 (m, 1H), 3.15 – 3.09 (m, 1H), 3.08 – 2.97 (m, 2H), 2.24 – 2.13 (m, 1H), 1.68 – 1.47 (m, 5H), 1.27 (d, J = 6.2 Hz , 3H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50mm, 3 µm; Hex w/0.1% DEA: EtOH = 50:50; Flow rate = 1.0 mL/min; rT = 1.981 min.

Example 20 Isomer B (20B) : 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine-2- (Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one (17.5 mg , 33% yield, white solid). LCMS (ESI, m/z): 551.20 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ: 13.22 (s, 1H), 8.69 (s, 2H), 8.30 (s, 1H), 5.22-5.12 (m, 1H), 4.86-4.77 (m, 2H) ), 4.11-3.99 (m, 2H), 3.89-3.82 (m, 1H), 3.77-3.70 (m, 1H), 3.25-3.17 (m, 1H), 3.16-3.08 (m, 1H), 3.07-2.98 (m, 2H), 2.28-2.17 (m, 1H), 1.75 – 1.47 (m, 5H), 1.27 (d, J = 6.2 Hz, 3H). Chiral HPLC: CHIRALPAK IA-3, 4.6*50mm, 3 µm; Hex w/0.1%DEA: EtOH = 50:50; Flow rate = 1.0 mL/min; rT = 2.695 min.

LCMS (ESI, m/z): 536.20 [M+H]⁺ 22A* 5-(((S)-1-(((S)-1-(1-(5-(二氟甲基)吡𠯤-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 532.2 [M+H]⁺ 22B* 5-(((S)-1-(((R)-1-(1-(5-(二氟甲基)吡𠯤-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 532.2 [M+H]⁺ 23 4-溴-5-(((S)-1-(((S)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 561.1 [M+H]⁺ 24 5-(((S)-1-(((R)-1-(1-(5-溴嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 561.1 [M+H]⁺ 25 (S)-N-甲基-2-(2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)氧基)丙氧基)-N-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)乙醯胺

LCMS (ESI, m/z): 539.2 [M+H]⁺ 26A^± 5-(((S)-1-(((S)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)胺基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 549.2 [M+H]⁺ 26B* 5-(((S)-1-(((R)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)胺基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 549.2 [M+H]⁺ 26C^± 5-(((R)-1-(((S)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)胺基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 549.2 [M+H]⁺ 26D^± 5-(((R)-1-(((R)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)胺基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 549.2 [M+H]⁺ 27 5-(((2S)-1-((1-(1-(5-(二氟甲基)嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)氧基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 533.2 [M+H]⁺ 28 (S)-2-(2-((5-溴-6-側氧基-1,6-二氫嗒𠯤-4-基)氧基)丙氧基)-N-甲基-N-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)乙醯胺

LCMS (ESI, m/z): 549.1 [M+H]⁺ 29 5-(((2S)-1-(甲基(2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)胺基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 563.2 [M+H]⁺ 30 6-(4-(2-側氧基-3-((S)-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)氧基)丙氧基)吡咯啶-1-基)六氫吡啶-1-基)菸鹼甲腈

LCMS (ESI, m/z): 507.2 [M+H]⁺ 31A* 5-(((S)-1-(((S)-2-側氧基-1-(1-(5-(三氟甲基)吡𠯤-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 551.2 [M+H]⁺ 31B* 5-(((S)-1-(((R)-2-側氧基-1-(1-(5-(三氟甲基)吡𠯤-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)-4-(三氟甲基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 551.2 [M+H]⁺ 32 4-溴-5-(((S)-1-(((R)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)胺基)嗒𠯤-3(2H)-酮

LCMS (ESI, m/z): 562.2 [M+H]⁺ 33A^± N-((3R,4R)-3-羥基-1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)-2-((S)-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)乙醯胺

LCMS (ESI, m/z): 540.2 [M+H]⁺ 33B^± N-((3S,4S)-3-羥基-1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)-2-((S)-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)乙醯胺

LCMS (ESI, m/z): 540.2 [M+H]⁺ *藉由類似於實例10、基於活性更大之非鏡像異構物之PARP7功效及類似於實例10B X-射線晶體結構分配化合物之立體化學。^± 任意地分配化合物之立體化學。The compounds of Examples 21-33B were synthesized similarly to the compounds described in Examples 1-20. Instance number name structure analyze data twenty one 4-(Trifluoromethyl)-5-(((2S)-1-((1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrole (Pyridin-3-yl)oxy)prop-2-yl)amino)pah-3(2H)-one

LCMS (ESI, m/z): 536.20 [M+H] ⁺ 22A* 5-(((S)-1-(((S)-1-(1-(5-(Difluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)-2-oxo (Pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 532.2 [M+H] ⁺ 22B* 5-(((S)-1-(((R)-1-(1-(5-(Difluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)-2-oxo (Pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 532.2 [M+H] ⁺ twenty three 4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one

LCMS (ESI, m/z): 561.1 [M+H] ⁺ twenty four 5-(((S)-1-(((R)-1-(1-(5-Bromopyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3- (Yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 561.1 [M+H] ⁺ 25 (S)-N-Methyl-2-(2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)oxy)propoxy )-N-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide

LCMS (ESI, m/z): 539.2 [M+H] ⁺ 26A ^± 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl) (Pyrrolidin-3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 549.2 [M+H] ⁺ 26B* 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl) (Pyrrolidin-3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 549.2 [M+H] ⁺ 26C ^± 5-(((R)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl) (Pyrrolidin-3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 549.2 [M+H] ⁺ 26D ^± 5-(((R)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl) (Pyrrolidin-3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 549.2 [M+H] ⁺ 27 5-(((2S)-1-((1-(1-(5-(Difluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -Yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 533.2 [M+H] ⁺ 28 (S)-2-(2-((5-Bromo-6-pendant oxy-1,6-dihydrota-4-yl)oxy)propoxy)-N-methyl-N-( 1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide

LCMS (ESI, m/z): 549.1 [M+H] ⁺ 29 5-(((2S)-1-(Methyl(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine -3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 563.2 [M+H] ⁺ 30 6-(4-(2-Pendant oxy-3-((S)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4-yl )Oxy)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile

LCMS (ESI, m/z): 507.2 [M+H] ⁺ 31A* 5-(((S)-1-(((S)-2-side oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl )Pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 551.2 [M+H] ⁺ 31B* 5-(((S)-1-(((R)-2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl )Pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one

LCMS (ESI, m/z): 551.2 [M+H] ⁺ 32 4-bromo-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)pado-3(2H)-one

LCMS (ESI, m/z): 562.2 [M+H] ⁺ 33A ^± N-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-((S)-2-(( 6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotetra-4-yl)amino)propoxy)acetamide

LCMS (ESI, m/z): 540.2 [M+H] ⁺ 33B ^± N-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-((S)-2-(( 6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotetra-4-yl)amino)propoxy)acetamide

LCMS (ESI, m/z): 540.2 [M+H] ⁺ *The stereochemistry of the compound is assigned by similar to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to the X-ray crystal structure of Example 10B. ^± Arbitrarily assign the stereochemistry of the compound.

Intermediate I-7: 3- hydroxy - [4'-linked piperidine] -2-one hydrochloride of the

Step A : Add K ₂ CO ₃ (2.08 g , 15.0 mmol, 1.5 equiv) and 5-bromopentyl chloride (2.00 g, 10.0 mmol, 1.0 equiv). The reaction mixture was stirred for 1 hour and diluted with water (20 mL) and extracted with 3×20 mL ethyl acetate. The combined organic extracts were washed with water (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 3.5 g (99% yield) of N-(1-benzylhexahydropyridine-4) as a white solid -Yl)-5-bromopentylamide. LCMS (ESI, m/z): 355.00 [M+H] ⁺ .

Step B Add t-BuOK ( 1.62 g, 14.4 mmol, 1.5 equiv). The reaction mixture was stirred for 1 hour and then quenched by adding water (20 mL). The resulting solution was extracted with 3 × 50 mL ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 2.5 g (95% yield) of 1'-benzyl-[ 1,4'-Bihexahydropyridine]-2-one. LCMS (ESI, m/z): 273.10 [M+H] ⁺ .

Step C Add TEMPO to a solution of 1'-benzyl-[1,4'-bihexahydropyridine]-2-one (2.00 g, 7.30 mmol, 1.0 equiv) in DCM (20 mL) at 0°C (2.50 g, 16.0 mmol, 2.2 equiv), 3Å molecular sieve (2 g) and Tf ₂ O (2.28 g, 8.08 mmol, 1.1 equiv). The resulting solution was stirred for 2 hours and then diluted with water (20 mL). The solution was extracted with 3×50 mL DCM, and the combined organic layer was dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (4/1) to obtain 1.5 g (48% yield) of a yellow oily 1'-benzyl-3-((2 ,2,6,6-Tetramethylhexahydropyridin-1-yl)oxy)-[1,4'-bihexahydropyridin]-2-one. LCMS (ESI, m/z): 428.20 [M+H] ⁺ .

Step D to 1'-benzyl-3-((2,2,6,6-tetramethylhexahydropyridin-1-yl)oxy)-[1,4'-bihexahydropyridine]-2- Add zinc powder (2.00 g, 30.6 mmol, 16 equiv) to a solution of ketone (800 mg, 1.87 mmol, 1.0 equiv) in a mixture of AcOH, THF and water (20 mL, 3:1:1). The resulting solution was stirred at 70°C for 1 hour. Dilute the solution with water (20 mL). Adjust the pH of the solution to 12 with saturated aqueous NaOH. After filtration, the filtrate was extracted with 3×50 mL ethyl acetate, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was applied to a silica gel column eluted with DCM/MeOH to obtain 300 mg (56% yield) of 1'-benzyl-3-hydroxy-[1,4'-dihexahydro Pyridin]-2-one. LCMS (ESI, m/z): 289.05 [M+H] ⁺ .

Step E Add Pd to a solution of 1'-benzyl-3-hydroxy-[1,4'-bihexahydropyridine]-2-one (400 mg, 1.4 mmol, 1.0 equiv) in EtOH (10 mL) /C (20 mg, 0.19 mmol, 0.1 equiv) and di-tertiary butyl dicarbonate (605 mg, 2.77 mmol, 2.0 equiv). The resulting solution was stirred for 1 hour under a hydrogen atmosphere. The solid was filtered, and the filtrate was concentrated in vacuo to obtain 380 mg (92% yield) of 3-hydroxy-2-oxo-[1,4'-bihexahydropyridine]-1'-acetic acid as a colorless oil Tertiary butyl ester. LCMS (ESI, m/z): 299.15 [M+H] ⁺ .

Step F: 3-Hydroxy-2-oxo-[1,4'-bihexahydropyridine]-1'-tert-butyl acetate (370 mg, 1.24 mmol, 1.0 equiv) in 4M dioxane The solution in HCl (10 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo to obtain 280 mg (96% yield) of 3-hydroxy-[1,4'-bihexahydropyridine]-2-one hydrochloride as a colorless oil. LCMS (ESI, m/z): 199.00 [M+H] ⁺ .

Intermediate I-8 : Synthesis of 3- hydroxy- 4,4 -dimethyl- 1-( hexahydropyridin- 4 -yl ) pyrrolidin -2- one hydrochloride

Step A: Add 1-benzylhexahydropyridine-4-amine (1.90 g, 9.99 mmol, 1.0 equiv) in 1-methoxy-2-(2-methoxyethoxy)ethane (1 mL) Add TsOH (0.28 g, 1.6 mmol, 0.2 equiv) and 3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (1.56 g, 12.0 mmol, 1.2 equiv) to the solution. The reaction mixture was irradiated with microwave radiation at 150°C for 1 hour. The resulting solution was stirred at 200°C for another 2 hours and then diluted with ethyl acetate (2 mL). The crude product was applied to a silica gel column eluted with dichloromethane/methanol (9/1) to obtain 840 mg (28% yield) of 1-(1-benzylhexahydropyridine-4) as a brown solid -Yl)-3-hydroxy-4,4-dimethylpyrrolidin-2-one. LC-MS (ES, m/z): 303.00 [M+H] ⁺ .

Step B Add 1-(1-benzylhexahydropyridin-4-yl)-3-hydroxy-4,4-dimethylpyrrolidin-2-one (837 mg, 2.77 mmol, 1.0 equiv) in EtOH (20 Add Pd/C (80 mg, 0.75 mmol, 0.3 equiv) and di-tertiary butyl dicarbonate (1.2 g, 5.5 mmol, 1.2 equiv) to the solution in mL). The resulting solution was stirred for 2 hours under a hydrogen atmosphere. After filtration, the filtrate was concentrated in vacuo, and the crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (9/1) to obtain 660 mg (76% yield) of white solid 4 -(3-Hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)tert-butyl hexahydropyridine-1-acetate. LC-MS (ES, m/z): 313.10 [M+H] ⁺

Step C Add 4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl) hexahydropyridine-1-acetic acid tert-butyl ester (660 mg, 2.11 mmol, 1.0 equiv ) Add 4M HCl (5 mL) in 1,4-dioxane to the solution in dioxane (5 mL). The resulting solution was stirred for 2 hours and then concentrated in vacuo to obtain 680 mg (91% yield) of 3-hydroxy-4,4-dimethyl-1-(hexahydropyridin-4-yl) as a yellow solid Pyrrolidin-2-one hydrochloride. LCMS (ESI, m/z): 213.15 [M+H] ⁺ .

Intermediate I-9 : Synthesis of (S)-3 -hydroxy- 1-( hexahydropyridin- 4 -yl ) pyrrolidin -2-one hydrochloride

Step A: Add (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)acetic acid (10.0 g, 57.4 mmol, 1.0 equiv) Add DCC (17.8 g, 86.3 mmol, 1.5 equiv), DMAP (701 mg, 5.74 mmol, 0.1 equiv) and ethane mercaptan (7.14 g, 115 mmol, 2 equiv) to the solution in DCM (150 mL) ). The resulting solution was stirred at 0°C for 10 min and then at room temperature for 10 hours. The solid was filtered, and the filtrate was concentrated in vacuo. The crude product was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (6/94) to obtain 5.8 g (47% yield) of colorless oil (S)-2-(2,2- S-ethyl dimethyl-5-oxo-1,3-dioxolan-4-yl)thioacetate.

Step B to (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl) thioacetate S-ethyl ester (5.80 g, 26.6 mmol , 1.0 equiv) Triethylsilane (4.60 g, 39.5 mmol, 1.5 equiv) and Pd/C (2.00 g, 18.8 mmol, 0.7 equiv) were added to the solution in DCM (100 mL). The resulting solution was stirred at 25°C for 3 hours. The solid was filtered, and the filtrate was concentrated in vacuo. The crude product was cooled, and the separated solid was collected, thereby obtaining 5 g of crude (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane-4-) as a colorless solid Base) acetaldehyde.

Step C Add (S)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)acetaldehyde (4.90 g, 30.9 mmol, 1.0 equiv) in Add tert-butyl 4-aminohexahydropyridine-1-acetate (9.31 g, 46.5 mmol, 1.5 equiv) and AcOH (3.72 g, 0.1 mmol, 2.0 equiv) to the solution in DCM (100 mL). The resulting solution was stirred for 1 hour, and then STAB (19.7 g, 93.0 mmol, 3.0 equiv) was added, and the reaction mixture was stirred for another 3 hours. A saturated aqueous NaHCO ₃ solution was added, and the aqueous layer was extracted with 2×50 mL DCM. The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with ethyl acetate/petroleum ether (30/70) to obtain 6 g (68% yield) of (S)-4-(3-hydroxy- 2-Pyrridine-1-yl)hexahydropyridine-1-acetate tert-butyl ester. LCMS (ESI, m/z): 285.20 [M+H] ⁺ .

Step D: Add (S)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetate (6.00 g, 0.02 mmol, 1.0 equiv) in dioxane The solution in 4M HCl (15 mL) in alkane was stirred for 1 hour and then concentrated to obtain 4.5 g (96% yield) of (S)-3-hydroxy-1-(hexahydropyridine-4- Yl)pyrrolidin-2-one hydrochloride. LCMS (ESI, m/z): 185.10 [M+H] ⁺ .

Intermediate I-11: (R) -1 - ((1R, 5S, 6s) -3- azabicyclo [3.1.0] hex-6-yl) -3-hydroxy-pyrrolidin-2-one as hydrogen chloride synthesis

Step A to (1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-tert-butyl acetate (2.00 g, 10.1 mmol, 1.0 equiv) in DCM ( 40 mL), add 2-[(4R)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl]acetaldehyde (5.00 g, 31.6 mmol , 3.1 equiv) and AcOH (0.20 g, 3.33 mmol, 0.3 equiv). The reaction mixture was stirred for 1 hour, and then STAB (4.10 g, 19.4 mmol, 1.9 equiv) was added, and the reaction was stirred for another 1.5 hours. The solution was washed with 2×50 mL NaHCO ₃ aqueous solution, and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was applied to a silica gel column eluted with ethyl acetate/MeOH (4/1) to obtain 600 mg (21% yield) of a yellow solid (1R,5S,6s)-6-(( R)-3-Hydroxy-2-oxopyrrolidin-1-yl)-3-azabicyclo[3.1.0]hexane-3-acetic acid tert-butyl ester. LCMS (ESI, m/z ): 283.15 [M+H] ⁺ .

In step B, (1R, 5S, 6s)-6-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-3-azabicyclo[3.1.0]hexane-3 -A solution of tert-butyl acetate (600 mg, 2.13 mmol, 1.0 equiv) in 4M HCl (5 mL) in dioxane was stirred for 1 hour. The mixture was concentrated to obtain 400 mg of (crude) (R)-1-((1R,5S,6s)-3-azabicyclo[3.1.0]hex-6-yl)-3-hydroxypyrrole as a yellow solid Pyridin-2-one hydrogen chloride. LCMS (ES, m/z ): 183.20 [M+H] ⁺ .

Intermediate I-12 : (3R,4S)-3 -hydroxy- 4 -methyl- 1-( hexahydropyridin- 4 -yl ) pyrrolidin -2- one hydrochloride and (3 S ,4 R )- synthesis of the hydrochloride salt of 4-methyl-1- (hexahydro-4-yl) 3-hydroxy-pyrrolidin-2-one

Step A : Add 1-benzylhexahydro to a solution of 4-methyldihydrofuran-2(3H)-one (5.30 g, 52.9 mmol, 1.0 equiv) in diethylene glycol dimethyl ether (4 mL) Pyridine-4-amine (15.1 g, 79.4 mmol, 1.5 equiv) and 4-toluenesulfonic acid (1.37 g, 7.94 mmol, 0.2 equiv). The resulting solution was stirred at 180°C for 16 hours and then diluted with 6 mL of ethyl acetate and applied to a silica gel column eluted with dichloromethane/methanol (87/13) to obtain 2.49 g (17% yield) ) Is a yellow oily 1-(1-benzylhexahydropyridin-4-yl)-4-methylpyrrolidin-2-one. LCMS (ESI, m/z): 273.05 [M+H] ⁺ .

Step B was added to 1-(1-benzylhexahydropyridin-4-yl)-4-methylpyrrolidin-2-one (3.10 g, 11.4 mmol, 1.0 equiv) in DCM ( Add 3Å molecular sieve (2 g), TEMPO (3.91 g, 25.0 mmol, 2.2 equiv) and Tf ₂ O (6.42 g, 22.8 mmol, 2.0 equiv) to the solution in 20 mL). The resulting solution was stirred for 30 min and then at room temperature for another 2 hours. The solid was filtered, and then the filtrate was concentrated and applied to a silica gel column eluted with dichloromethane/methanol (97/3) to obtain 1.3 g (20% yield) of a yellow solid (3R, 4S)-1 -(1-Benzylhexahydropyridin-4-yl)-4-methyl-3-((2,2,6,6-tetramethylhexahydropyridin-1-yl)oxy)pyrrolidine-2 -Kone and (3S,4R)-1-(1-benzylhexahydropyridin-4-yl)-4-methyl-3-((2,2,6,6-tetramethylhexahydropyridine-1 -Yl)oxy)pyrrolidin-2-one. LCMS (ESI, m/z): 428.30 [M+H]+.

Step C to (3R, 4S)-1-(1-benzylhexahydropyridine-4-yl)-4-methyl-3-((2,2,6,6-tetramethylhexahydropyridine-1 -Yl)oxy)pyrrolidin-2-one and (3S,4R)-1-(1-benzylhexahydropyridin-4-yl)-4-methyl-3-((2,2,6, 6-Tetramethylhexahydropyridin-1-yl)oxy)pyrrolidin-2-one (1.30 g, 3.04 mmol, 1.0 equiv) in AcOH/THF/water (15 mL, 3:1:1) Zn (3.98 g, 60.8 mmol, 20 equiv) was added to the mixture. The resulting solution was stirred at 70°C for 2 hours and then diluted with water (15 mL). The pH was adjusted to 12 with aqueous NaOH and extracted with 3×30 mL ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with dichloromethane/methanol (93/7) to obtain 180 mg (21% yield) of yellow oily (3R,4S)-1-(1-benzyl) Hexahydropyridin-4-yl)-3-hydroxy-4-methylpyrrolidin-2-one and (3S,4R)-1-(1-benzylhexahydropyridin-4-yl)-3-hydroxy -4-Methylpyrrolidin-2-one. LCMS (ESI, m/z): 289.20 [M+H] ⁺ .

Step D To (3R,4S)-1-(1-benzylhexahydropyridin-4-yl)-3-hydroxy-4-methylpyrrolidin-2-one and (3S,4R)-1-(1 -Benzylhexahydropyridin-4-yl)-3-hydroxy-4-methylpyrrolidin-2-one in MeOH (4 mL) was added di-tert-butyl dicarbonate (272 mg, 1.25 mmol , 2.0 equiv) and Pd/C (7 mg, 0.06 mmol, 0.1 equiv). The resulting solution was stirred for 1 hour under a hydrogen atmosphere. The solid was filtered and the filtrate was concentrated to obtain 226 mg of crude (3R,4S)-4-(3-hydroxy-4-methyl-2-oxopyrrolidin-1-yl)hexahydropyridine-1- as a yellow oil Tert-butyl acetate and (3S,4R)-4-(3-hydroxy-4-methyl-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetate. LCMS (ESI, m/z): 299.05 [M+H] ⁺ .

In step E, crude (3R, 4S)-4-(3-hydroxy-4-methyl-2-oxopyrrolidin-1-yl) hexahydropyridine-1-acetic acid tert-butyl ester and (3S, 4R )-4-(3-hydroxy-4-methyl-2-oxopyrrolidin-1-yl)tert-butyl hexahydropyridine-1-acetate (226 mg, 0.76 mmol, 1.0 equiv) in HCl/ The solution in dioxane (10 mL, 4 M) was stirred for 1 hour and then concentrated to obtain 168 mg of crude (3R,4S)-3-hydroxy-4-methyl-1-(hexahydropyridine- 4-yl)pyrrolidin-2-one hydrochloride and (3S,4R)-3-hydroxy-4-methyl-1-(hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride. LCMS (ESI, m/z): 199.05 [M+H] ⁺ .

Intermediate I-13 : (R)-1-((3R,4R)-3- fluorohexahydropyridin- 4 -yl )-3 -hydroxypyrrolidin- 2- one- TFA salt and (R)-1- Synthesis of ((3S,4S)-3- fluorohexahydropyridin- 4 -yl )-3 -hydroxypyrrolidin- 2- one- TFA salt

Step A To (3R, 4R)-4-amino-3-fluorohexahydropyridine-1-acetic acid tert-butyl ester and (3S,4S)-4-amino-3-fluorohexahydropyridine-1-acetic acid The tertiary butyl ester (1.00 g, 4.51 mmol, 1.0 equiv) in DCM (20 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3- Dioxolane-4-yl)acetaldehyde (1.10 g, 6.96 mmol, 1.5 equiv) and AcOH (1.70 g, 0.03 mmol, 0.01 equiv). The resulting solution was stirred for 1 hour, and then STAB (2.90 g, 0.01 mmol, 3.0 equiv) was added, and the reaction mixture was stirred for another 3 hours. The reaction was quenched by adding saturated aqueous NaHCO _{3 solution.} The aqueous layer was extracted with 2×50 mL DCM. The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with MeOH/DCM (5/95) to obtain 700 mg (51% yield) of (3R,4R)-3-fluoro-4-(( R)-3-Hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetic acid tert-butyl ester and (3S,4S)-3-fluoro-4-((R)-3- Hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetate tert-butyl ester.

Step B adds (3R,4R)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetate and (3S ,4S)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetate (700 mg, 2.32 mmol, 1.0 equiv) Add TFA (0.5 mL) to the solution in DCM (5 mL). The resulting solution was stirred for 1 hour and then concentrated to obtain 600 mg of crude (R)-1-((3R,4R)-3-fluorohexahydropyridin-4-yl)-3-hydroxypyrrolidine-2 as a brown oil -Keto-TFA salt and (R)-1-((3S,4S)-3-fluorohexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one-TFA salt.

Intermediate I-14 : (R)-1-((3 R ,4 S )-3- fluorohexahydropyridin- 4 -yl )-3 -hydroxypyrrolidin- 2- one hydrochloride and ( R)- Synthesis of 1-((3S,4R)-3- fluorohexahydropyridin- 4 -yl )-3 -hydroxypyrrolidin- 2-one hydrochloride

Step A to (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)acetaldehyde (2.90 g, 18.34 mmol, 4.0 equiv) Add AcOH (550 mg, 9.16 mmol, 2.0 equiv) and (3S,4R)-4-amino-3-fluorohexahydropyridine-1-acetic acid tert-butyl ester and (3R) to the solution in DCM (20 mL) ,4S)-4-amino-3-fluorohexahydropyridine-1-tert-butyl acetate mixture (1.00 g, 4.51 mmol, 1.0 equiv). The resulting solution was stirred for 0.5 hour, and then STAB (2.91 g, 13.74 mmol, 3.0 equiv) was added, and the reaction was stirred for another 3 hours. The reaction was then quenched by adding 20 mL of NaHCO ₃ aqueous solution. The resulting solution was extracted with 3 × 50 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with dichloromethane/methanol (2/3) to obtain 0.66 g (48% yield) of yellow oil (3S,4R)-3-fluoro-4- ((R)-3-Hydroxy-2-pyrrolidin-1-yl)hexahydropyridine-1-acetate and (3R,4S)-3-fluoro-4-((R)- 3-Hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetate tert-butyl ester. LCMS (ESI, m/z): 303.15 [M+H] ⁺ .

Step B combines (3S,4R)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetate and (3R) ,4S)-3-fluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1-acetate (660 mg, 2.18 mmol, 1.0 The solution of equiv) in HCl/dioxane (15 mL, 4 M) was stirred for 15 hours. The resulting mixture was concentrated to obtain 510 mg (98% yield) of (R)-1-((3R,4S)-3-fluorohexahydropyridin-4-yl)-3-hydroxypyrrolidine-2 as a yellow oil -Ketone hydrochloride and (R)-1-((3S,4R)-3-fluorohexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one hydrochloride. LCMS (ESI, m/z): 203.15 [M+H] ⁺ .

Intermediate I-15 : (R)-1-((R)-3,3 -difluorohexahydropyridin- 4 -yl )-3 -hydroxypyrrolidin- 2- one hydrochloride and ( R)-1 -((S)-3,3 -Difluorohexahydropyridin- 4 -yl )-3 -hydroxypyrrolidin- 2- one hydrochloride

Step A To 4-amino-3,3-difluorohexahydropyridine-1-tert-butyl acetate (1.00 g, 4.23 mmol, 1.0 equiv) in DCM (50 mL) was added (R)- 2-(2,2-Dimethyl-5-oxo-1,3-dioxolane-4-yl)acetaldehyde (1004 mg, 6.35 mmol, 1.5 equiv), STAB (3.59 g, 16.9 mmol , 4.0 equiv) and AcOH (250 mg, 4.2 mmol, 1.0 equiv). The resulting solution was stirred for 12 hours and concentrated in vacuo. The crude product was applied to a silica gel column eluted with DCM/methanol (9/1) to obtain 1.5 g (crude) 3,3-difluoro-4-((R)-3-hydroxy- 2-Pyrridine-1-yl)hexahydropyridine-1-acetate tert-butyl ester. LCMS (ESI, m/z): 321.30 [M+H] ⁺ .

In step B, 3,3-difluoro-4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl) hexahydropyridine-1-acetate (1.50 g, 4.68 mmol , 1.0 equiv) in 4M HCl (10 mL) in dioxane was stirred for 6 hours and then concentrated in vacuo to obtain 1.5 g (crude) yellow oil (R)-1-((R)- 3,3-Difluorohexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one hydrochloride and (R)-1-((S)-3,3-difluorohexahydropyridine-4 -Yl)-3-hydroxypyrrolidin-2-one hydrochloride. LCMS (ESI, m/z): 221.10 [M+H] ⁺ .

向5-氯-2-(4-甲氧基苄基)-4-(三氟甲基)嗒𠯤-3(2H)-酮(2.00 g, 6.28 mmol, 1.0 equiv)於DMF (15 mL)中之溶液中添加L-丙胺酸(725 mg, 8.14 mmol, 1.3 equiv)及K₂ CO₃ (2.60 g, 18.8 mmol, 3.0 equiv)。將所得溶液於60℃下攪拌2小時，且然後藉由添加100 mL水淬滅。用1N HCl將pH調整至2-3。用3 × 150 mL DCM萃取溶液。合併有機層，經無水硫酸鈉乾燥且在真空中濃縮。將粗產物施加至用水/CH₃ CN (1/1)溶析之反相管柱上，從而得到1.4 g (60%產率)之淺黃色固體狀(1-(4-甲氧基苄基)-6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)-L-丙胺酸。LCMS (ES, m/z): 372.11 [M+H]⁺ 。 Intermediate I-16: (1- (4- methoxybenzyl) -6-oxo-5- (trifluoromethyl) -1,6-dihydropyridazine 𠯤 4-yl) -L- Synthesis of Alanine

To 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)- 3(2H)-one (2.00 g, 6.28 mmol, 1.0 equiv) in DMF (15 mL) Add L-alanine (725 mg, 8.14 mmol, 1.3 equiv) and K ₂ CO ₃ (2.60 g, 18.8 mmol, 3.0 equiv) to the solution in. The resulting solution was stirred at 60°C for 2 hours, and then quenched by adding 100 mL of water. Adjust the pH to 2-3 with 1N HCl. The solution was extracted with 3 × 150 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a _{reversed-phase column eluted with water/CH 3} CN (1/1) to obtain 1.4 g (60% yield) of light yellow solid (1-(4-methoxybenzyl) )-6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)-L-alanine. LCMS (ES, m/z): 372.11 [M+H] ⁺ .

(S)-3-((S)-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)-1'-(5-(三氟甲基)嘧啶-2-基)-[1,4'-聯六氫吡啶]-2-酮    LCMS (ESI, m/z): 564.20 [M+H]⁺ ；¹ H NMR (300 MHz, DMSO-d 6) δ: 12.42 (s, 1H), 8.69 (d,J = 0.9 Hz, 2H), 7.92 (s, 1H), 6.48 (br, 1H), 4.83 (d,J   = 12.9 Hz, 1H), 4.57 – 4.45 (m, 1H), 4.20 – 4.00 (m, 1H), 3.86 – 3.78 (m, 2H), 3.62 – 3.53 (m, 1H), 3.20 – 2.90 (m,  4H), 1.95 – 1.51 (m, 8H), 1.16 (d,J = 6.3 Hz, 3H)。 34B   

(R)-3-((S)-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)-1'-(5-(三氟甲基)嘧啶-2-基)-[1,4'-聯六氫吡啶]-2-酮    LCMS (ESI, m/z): 564.20 [M+H]⁺ ；¹ H NMR (300 MHz, DMSO-d 6) δ: 12.45 (s, 1H), 8.69 (d,J = 0.9 Hz, 2H), 7.94 (s, 1H), 6.47 (br, 1H), 4.84 (d,J   = 12.9 Hz, 1H), 4.65 – 4.35 (m, 1H), 4.22 – 4.01 (m, 1H), 3.89 – 3.72 (m, 2H), 3.68 – 3.58 (m, 1H), 3.15 – 2.90 (m,  4H), 2.00 – 1.47 (m, 8H), 1.15 (d,J = 6.3 Hz, 3H)。    35A   

5-(((S)-1-(((S)-4,4-二甲基-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮    LCMS (ESI, m/z): 578.30 [M+H]⁺ ；¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.38 (s, 1H), 8.69 (s, 2H), 7.93 (s, 1H), 6.39 (br, 1H), 4.80 (d,J = 13.2 Hz, 2H), 4.27 – 4.21 (m, 1H), 4.09 – 4.03 (m, 2H), 3.65 (s, 1H), 3.59 – 3.55 (m, 1H), 3.09 – 3.00 (m, 2H), 2.91 (s, 2H), 1.67 – 1.46 (m, 4H), 1.17 (d,J = 6.5 Hz, 3H), 1.00 (s, 3H), 0.77 (s, 3H)。 35B   

5-(((S)-1-(((R)-4,4-二甲基-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 578.30 [M+H]⁺ ；¹ H NMR (400 MHz, DMSO-d₆ ) δ 12.45 (s, 1H), 8.69 (s, 2H), 7.95 (s, 1H), 6.30 (br, 1H), 4.80 (d,J = 13.2 Hz, 2H), 4.26 – 4.18 (m, 1H), 4.10 – 4.04 (m, 1H), 4.00 – 3.96 (m, 1H), 3.68 – 3.63 (m, 2H), 3.07 – 3.00 (m, 2H), 2.92 (s, 2H), 1.66 – 1.48 (m, 4H), 1.19 (d,J = 6.4 Hz, 3H), 1.04 (s, 3H), 0.85 (s, 3H)。 36A   

(R)-6-(4-(2-側氧基-3-(2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)乙氧基)吡咯啶-1-基)六氫吡啶-1-基)菸鹼甲腈 LCMS (ESI, m/z): 492.25 [M+H]⁺ 36B   

(S)-6-(4-(2-側氧基-3-(2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)乙氧基)吡咯啶-1-基)六氫吡啶-1-基)菸鹼甲腈 LCMS (ESI, m/z): 492.25 [M+H]⁺ 37A   

5-(((S)-1-(((3S,4R)-4-甲基-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 564.20 [M+H]⁺ 37B   

5-(((S)-1-(((3R,4S)-4-甲基-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 564.20 [M+H]⁺ Examples 34-37 Examples 34-37 are based on 5-((S)-1-((S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4 -Yl)-2-side oxypyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl )- 3(2 H )-one and 5-(( S)-1-((R)-1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl (Oxy)propan-2-ylamino)-4-(trifluoromethyl)pado-3( 2H )-one described in the procedure (see Example 10), use appropriate building elements and Synthesize by modifying reaction conditions (such as reagent ratio, temperature, coupling conditions, and reaction time). The relative stereochemistry of the compound is assigned by analogy to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure. Instance number structure analyze data 34A

(S)-3-((S)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy) -1'-(5-(Trifluoromethyl)pyrimidin-2-yl)-[1,4'-bihexahydropyridine]-2-one LCMS (ESI, m/z): 564.20 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d 6) δ: 12.42 (s, 1H), 8.69 (d, J = 0.9 Hz, 2H), 7.92 (s, 1H), 6.48 (br, 1H), 4.83 (d, J = 12.9 Hz, 1H), 4.57 – 4.45 (m, 1H), 4.20 – 4.00 (m, 1H), 3.86 – 3.78 (m, 2H), 3.62 – 3.53 (m, 1H), 3.20 – 2.90 (m, 4H), 1.95 – 1.51 (m, 8H), 1.16 (d, J = 6.3 Hz, 3H). 34B

(R)-3-((S)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy) -1'-(5-(Trifluoromethyl)pyrimidin-2-yl)-[1,4'-bihexahydropyridine]-2-one LCMS (ESI, m/z): 564.20 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d 6) δ: 12.45 (s, 1H), 8.69 (d, J = 0.9 Hz, 2H), 7.94 (s, 1H), 6.47 (br, 1H), 4.84 (d, J = 12.9 Hz, 1H), 4.65 – 4.35 (m, 1H), 4.22 – 4.01 (m, 1H), 3.89 – 3.72 (m, 2H), 3.68 – 3.58 (m, 1H), 3.15 – 2.90 (m, 4H), 2.00 – 1.47 (m, 8H), 1.15 (d, J = 6.3 Hz, 3H). 35A

5-(((S)-1-(((S)-4,4-dimethyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl) (Hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 578.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.38 (s, 1H), 8.69 (s, 2H), 7.93 (s, 1H) , 6.39 (br, 1H), 4.80 (d, J = 13.2 Hz, 2H), 4.27 – 4.21 (m, 1H), 4.09 – 4.03 (m, 2H), 3.65 (s, 1H), 3.59 – 3.55 (m , 1H), 3.09 – 3.00 (m, 2H), 2.91 (s, 2H), 1.67 – 1.46 (m, 4H), 1.17 (d, J = 6.5 Hz, 3H), 1.00 (s, 3H), 0.77 ( s, 3H). 35B

5-(((S)-1-(((R)-4,4-dimethyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl) (Hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 578.30 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.45 (s, 1H), 8.69 (s, 2H), 7.95 (s, 1H) , 6.30 (br, 1H), 4.80 (d, J = 13.2 Hz, 2H), 4.26 – 4.18 (m, 1H), 4.10 – 4.04 (m, 1H), 4.00 – 3.96 (m, 1H), 3.68 – 3.63 (m, 2H), 3.07 – 3.00 (m, 2H), 2.92 (s, 2H), 1.66 – 1.48 (m, 4H), 1.19 (d, J = 6.4 Hz, 3H), 1.04 (s, 3H), 0.85 (s, 3H). 36A

(R)-6-(4-(2-Pendant oxy-3-(2-((6-Pendent oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4-yl )Amino)ethoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile LCMS (ESI, m/z): 492.25 [M+H] ⁺ 36B

(S)-6-(4-(2-Pendant oxy-3-(2-((6-Pendent oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl )Amino)ethoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile LCMS (ESI, m/z): 492.25 [M+H] ⁺ 37A

5-(((S)-1-(((3S,4R)-4-methyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa (Hydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 564.20 [M+H] ⁺ 37B

5-(((S)-1-(((3R,4S)-4-methyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa (Hydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 564.20 [M+H] ⁺

5-(((S)-1-(((R)-1-((3R,4R)-3-氟-1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 568.20 [M+H]⁺ 38B   

5-(((S)-1-(((R)-1-((3S,4S)-3-氟-1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 568.20 [M+H]⁺ ； 39A   

5-(((S)-1-(((R)-1-((3S,4R)-3-氟-1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 568.15 [M+H]⁺ ；¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.46 (s, 1H), 8.71 (s, 2H), 7.95 (s, 1H), 6.33 - 6.31 (m, 1H), 5.08 (t,J = 11.6 Hz, 1H), 4.97 - 4.86 (m, 2H), 4.29 -4.13 (m, 3H), 3.83 (dd,J = 10.0, 6.3 Hz, 1H), 3.62 (dd,J = 10.0, 4.8 Hz, 1H), 3.43 - 3.33 (m, 2H), 3.30 – 3.24 (m, 1H), 3.19 (t,J = 12.6 Hz, 1H), 2.33 - 2.23 (m, 1H), 2.02 – 1.89 (m, 1H), 1.84 – 1.74 (m, 1H), 1.68 - 1.62 (m, 1H), 1.18 (d,J = 6.4 Hz, 3H)。 39B   

5-(((S)-1-(((R)-1-((3R,4S)-3-氟-1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 568.10 [M+H]⁺ ；¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.46 (s, 1H), 8.71 (s, 2H), 7.95 (s, 1H), 6.32 - 6.30 (m, 1H),5.09 (t,J = 11.6 Hz, 1H), 4.98 – 4.83 (m, 2H), 4.37 – 4.14 (m, 3H), 3.83 (dd,J = 10.0, 6.5 Hz, 1H), 3.62 (dd,J = 10.0, 4.7 Hz, 1H), 3.45 – 3.35 (m, 1H), 3.33 - 3.30  (m, 1H), 3.28 – 3.12 (m, 2H), 2.33 - 2.23 (m, 1H), 2.02 – 1.89 (m, 1H), 1.84 – 1.74 (m, 1H), 1.68 - 1.62 (m, 1H), 1.18 (d,J = 6.4 Hz, 3H)。 40A   

6-((R)-3,3-二氟-4-((R)-2-側氧基-3-((S)-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)吡咯啶-1-基)六氫吡啶-1-基)菸鹼甲腈 LCMS (ESI, m/z): 542.15 [M+H]⁺ ；¹ H NMR (300 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.50 (d,J = 2.1 Hz, 1H), 7.94(s, 1H),7.92 – 7.89 (m, 1H), 7.11 (d,J = 9.2 Hz, 1H), 6.31- 6.26 (m, 1H), 4.90-4.88 (m, 1H), 4.70-4.50 (m, 2H), 4.25-4.12 (m, 2H), 3.90-3.80 (m, 1H), 3.70 – 3.65 (m, 1H), 3.55 -3.45(m, 1H), 3.43-3.38 (m, 2H), 3.29-3.22 (m, 1H), 2.28-2.20 (m, 1H),  1.85-1.72 (m, 3H), 1.16 (d,J = 6.5 Hz, 3H)。 40B   

6-((S)-3,3-二氟-4-((R)-2-側氧基-3-((S)-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)吡咯啶-1-基)六氫吡啶-1-基)菸鹼甲腈 LCMS (ESI, m/z): 542.15 [M+H]⁺ ；¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.44 (s, 1H), 8.50 (d,J = 2.3 Hz, 1H), 7.96(s, 1H)7.94-7.85 (m, 1H), 7.11 (d,J = 9.1 Hz, 1H), 6.31 -6.25(m, 1H), 4.87-4.80(m, 1H), 4.72-4.65 (m，2H), 4.35 -4.22(m, 2H), 3.85-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.55-3.35 (m, 2H), 3.31-3.17 (m, 2H), 2.32-2.28 (m, 1H), 2.02-1.90 (m, 1H), 1.73-1.67 (m, 2H), 1.16 (d,J = 6.4 Hz, 3H)。 Examples 38-40 Examples 38-40 are based on 5-((S)-1-((S)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4 -Yl)-2-side oxypyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl )- 3(2 H )-one and 5-(( S)-1-((R)-1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl (Oxy)propan-2-ylamino)-4-(trifluoromethyl)pado-3(2H)-one described in the procedure (see Example 10), use appropriate construction components and economics as needed Modify the reaction conditions (such as reagent ratio, temperature, coupling conditions and reaction time) to synthesize. Arbitrarily assign the absolute stereochemistry of the substituted hexahydropyridine moiety. Instance number structure analyze data 38A

5-(((S)-1-(((R)-1-((3R,4R)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 568.20 [M+H] ⁺ 38B

5-(((S)-1-(((R)-1-((3S,4S)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 568.20 [M+H] ⁺ ; 39A

5-(((S)-1-(((R)-1-((3S,4R)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 568.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.46 (s, 1H), 8.71 (s, 2H), 7.95 (s, 1H) , 6.33-6.31 (m, 1H), 5.08 (t, J = 11.6 Hz, 1H), 4.97-4.86 (m, 2H), 4.29 -4.13 (m, 3H), 3.83 (dd, J = 10.0, 6.3 Hz , 1H), 3.62 (dd, J = 10.0, 4.8 Hz, 1H), 3.43-3.33 (m, 2H), 3.30-3.24 (m, 1H), 3.19 (t, J = 12.6 Hz, 1H), 2.33- 2.23 (m, 1H), 2.02 – 1.89 (m, 1H), 1.84 – 1.74 (m, 1H), 1.68-1.62 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H). 39B

5-(((S)-1-(((R)-1-((3R,4S)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 568.10 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.46 (s, 1H), 8.71 (s, 2H), 7.95 (s, 1H) , 6.32-6.30 (m, 1H), 5.09 (t, J = 11.6 Hz, 1H), 4.98 – 4.83 (m, 2H), 4.37 – 4.14 (m, 3H), 3.83 (dd, J = 10.0, 6.5 Hz , 1H), 3.62 (dd, J = 10.0, 4.7 Hz, 1H), 3.45 – 3.35 (m, 1H), 3.33-3.30 (m, 1H), 3.28 – 3.12 (m, 2H), 2.33-2.23 (m , 1H), 2.02 – 1.89 (m, 1H), 1.84 – 1.74 (m, 1H), 1.68-1.62 (m, 1H), 1.18 (d, J = 6.4 Hz, 3H). 40A

6-((R)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl) (Yl)-1,6-dihydropyridine-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile LCMS (ESI, m/z): 542.15 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.50 (d, J = 2.1 Hz, 1H), 7.94( s, 1H),7.92 – 7.89 (m, 1H), 7.11 (d, J = 9.2 Hz, 1H), 6.31- 6.26 (m, 1H), 4.90-4.88 (m, 1H), 4.70-4.50 (m, 2H), 4.25-4.12 (m, 2H), 3.90-3.80 (m, 1H), 3.70 – 3.65 (m, 1H), 3.55 -3.45(m, 1H), 3.43-3.38 (m, 2H), 3.29- 3.22 (m, 1H), 2.28-2.20 (m, 1H), 1.85-1.72 (m, 3H), 1.16 (d, J = 6.5 Hz, 3H). 40B

6-((S)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl) )-1,6-Dihydropyridine-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile LCMS (ESI, m/z): 542.15 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.44 (s, 1H), 8.50 (d, J = 2.3 Hz, 1H), 7.96 (s, 1H)7.94-7.85 (m, 1H), 7.11 (d, J = 9.1 Hz, 1H), 6.31 -6.25(m, 1H), 4.87-4.80(m, 1H), 4.72-4.65 (m, 2H), 4.35 -4.22(m, 2H), 3.85-3.80 (m, 1H), 3.70-3.63 (m, 1H), 3.55-3.35 (m, 2H), 3.31-3.17 (m, 2H), 2.32- 2.28 (m, 1H), 2.02-1.90 (m, 1H), 1.73-1.67 (m, 2H), 1.16 (d, J = 6.4 Hz, 3H).

5-(((S)-1-(((R)-1-(1-(5-氯吡𠯤-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 516.10 [M+H]⁺ 42   

5-(((S)-1-(((R)-1-(1-(5-氟嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 500.20 [M+H]⁺ 43   

5-(((S)-1-(((R)-2-側氧基-1-((1R,5S,6s)-3-(5-(三氟甲基)嘧啶-2-基)-3-氮雜二環[3.1.0]己-6-基)吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 548.20 [M+H]⁺ 44

5-(((S)-1-(((R)-1-(1-(5-甲基嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 496.52 [M+H]⁺ ；¹ H NMR (400 MHz, CDCl₃ ) δ ppm 1.25 (s, 2 H) 1.33 (br d,J = 6.36 Hz, 4 H) 1.44 (br s, 1 H) 1.50 - 1.60 (m, 5 H) 1.63 - 1.75 (m, 3 H) 1.92 (br dd,J = 14.18, 7.34 Hz, 1 H) 2.03 (s, 1 H) 2.12 (s, 3 H) 2.28 - 2.38 (m, 1 H) 2.87 - 2.97 (m, 2 H) 3.15 - 3.23 (m, 1 H) 3.28 - 3.36 (m, 1 H) 3.71 (br dd,J = 9.78, 4.40 Hz, 1 H) 3.91 - 4.00 (m, 1 H) 4.05 (t,J = 7.58 Hz, 1 H) 4.13 - 4.26 (m, 2 H) 4.84 (br dd,J = 9.54, 2.69 Hz, 2 H) 5.96 (br s, 1 H) 7.70 (s, 1 H) 8.15 (s, 2 H)。 45   

5-(4-((R)-2-側氧基-3-((S)-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)吡咯啶-1-基)六氫吡啶-1-基)吡𠯤-2-甲腈 LCMS (ESI, m/z): 507.43 [M+H]⁺ ；¹ H NMR (CDCl₃ , 400 MHz) δ 10.46 (br s, 1H), 8.32 (s, 1H), 8.15 (s, 1H), 7.71 (s, 1H), 5.8-6.0 (m, 1H), 4.60 (br t, 2H,J = 14.7 Hz), 4.26 (tt, 1H,J = 4.3, 12.1 Hz), 4.1-4.2 (m, 1H), 4.05 (dd, 1H,J = 6.6, 7.6 Hz), 3.9-4.0 (m, 1H), 3.73 (dd, 1H,J = 3.9, 9.8 Hz), 3.30 (dt, 1H,J = 4.4, 9.0 Hz), 3.2-3.2 (m, 1H), 3.0-3.1 (m, 2H), 2.3-2.4 (m, 1H), 1.9-2.0 (m, 1H), 1.83 (br d, 2H,J = 11.7 Hz), 1.6-1.7 (m, 2H), 1.5-1.6 (m, 1H), 1.32 (d, 3H, J=6.8 Hz), 1.25 (s, 2H)。 Examples 41-45 Examples 41-45 are based on 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl) -2-Pyrridine-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one The procedure described in the synthesis ( See Example 16). If necessary, use appropriate construction components and modified reaction conditions (such as reagent ratio, temperature, coupling conditions, and reaction time) to synthesize. Instance number structure analyze data 41

5-(((S)-1-(((R)-1-(1-(5-chloropyridine-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -Yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 516.10 [M+H] ⁺ 42

5-(((S)-1-(((R)-1-(1-(5-fluoropyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3- (Yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 500.20 [M+H] ⁺ 43

5-(((S)-1-(((R)-2-oxo-1-((1R,5S,6s)-3-(5-(trifluoromethyl)pyrimidin-2-yl) -3-Azabicyclo[3.1.0]hex-6-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3 (2H)-ketone LCMS (ESI, m/z): 548.20 [M+H] ⁺ 44

5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -Yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 496.52 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.25 (s, 2 H) 1.33 (br d, J = 6.36 Hz, 4 H) 1.44 (br s, 1 H) 1.50-1.60 (m, 5 H) 1.63-1.75 (m, 3 H) 1.92 (br dd, J = 14.18, 7.34 Hz, 1 H) 2.03 (s, 1 H) 2.12 (s , 3 H) 2.28-2.38 (m, 1 H) 2.87-2.97 (m, 2 H) 3.15-3.23 (m, 1 H) 3.28-3.36 (m, 1 H) 3.71 (br dd, J = 9.78, 4.40 Hz, 1 H) 3.91-4.00 (m, 1 H) 4.05 (t, J = 7.58 Hz, 1 H) 4.13-4.26 (m, 2 H) 4.84 (br dd, J = 9.54, 2.69 Hz, 2 H) 5.96 (br s, 1 H) 7.70 (s, 1 H) 8.15 (s, 2 H). 45

5-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro) -4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)pyridine-2-carbonitrile LCMS (ESI, m/z): 507.43 [M+H] ⁺ ; ¹ H NMR (CDCl ₃ , 400 MHz) δ 10.46 (br s, 1H), 8.32 (s, 1H), 8.15 (s, 1H), 7.71 (s, 1H), 5.8-6.0 (m, 1H), 4.60 (br t, 2H, J = 14.7 Hz), 4.26 (tt, 1H, J = 4.3, 12.1 Hz), 4.1-4.2 (m, 1H ), 4.05 (dd, 1H, J = 6.6, 7.6 Hz), 3.9-4.0 (m, 1H), 3.73 (dd, 1H, J = 3.9, 9.8 Hz), 3.30 (dt, 1H, J = 4.4, 9.0 Hz), 3.2-3.2 (m, 1H), 3.0-3.1 (m, 2H), 2.3-2.4 (m, 1H), 1.9-2.0 (m, 1H), 1.83 (br d, 2H, J = 11.7 Hz ), 1.6-1.7 (m, 2H), 1.5-1.6 (m, 1H), 1.32 (d, 3H, J=6.8 Hz), 1.25 (s, 2H).

4-溴-5-(((S)-1-(((S)-2-側氧基-1-(1-(5-(三氟甲基)吡𠯤-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 563.10 [M+H]⁺ ； 1H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.69 (d,J = 0.9 Hz, 2H), 7.92 (s, 1H), 6.48 (br s, 1H), 4.83 (d,J   = 12.9 Hz, 1H), 4.57 – 4.45 (m, 1H), 4.20 – 4.00 (m, 1H), 3.86 – 3.78 (m, 2H), 3.62 – 3.53 (m, 1H), 3.20 – 2.90 (m,  4H), 1.95 – 1.51 (m, 8H), 1.16 (d,J = 6.3 Hz, 3H)。 46B   

4-溴-5-(((S)-1-(((R)-2-側氧基-1-(1-(5-(三氟甲基)吡𠯤-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)嗒𠯤-3(2H)-酮    LCMS (ESI, m/z): 563.10 [M+H]⁺ ； 1H NMR (300 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.69 (d,J = 0.9 Hz, 2H), 7.94 (s, 1H), 6.47 (br s, 1H), 4.84 (d,J   = 12.9 Hz, 1H), 4.65 – 4.35 (m, 1H), 4.22 – 4.01 (m, 1H), 3.89 – 3.72 (m, 2H), 3.68 – 3.58 (m, 1H), 3.15 – 2.90 (m,  4H), 2.00 – 1.47 (m, 8H), 1.15 (d,J = 6.3 Hz, 3H)。 47A   

4-氯-5-(((S)-1-(((S)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 517.10 [M+H]⁺ ；¹ H NMR(300 MHz, DMSO-d ₆ ) δ 13.22 (s, 1H), 8.70 (s, 2H), 8.21 (s, 1H), 5.30 – 5.10 (m, 1H), 4.83 (d,J = 13.5 Hz, 2H), 4.21 – 3.90 (m, 3H), 3.72 – 3.61 (m, 1H), 3.25 – 2.98 (m, 4H), 2.27 – 2.06 (m, 1H), 1.72 – 1.48 (m, 5H), 1.29 (d,J = 6.3 Hz, 3H)。 47B   

4-氯-5-(((S)-1-(((R)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 517.10 [M+H]⁺ ；¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.22 (s, 1H), 8.70 (s, 2H), 8.23 (s, 1H), 5.11 – 4.99 (m, 1H), 4.82 (d,J = 13.4 Hz, 2H), 4.17 -3.99 (m, 2H), 3.98 – 3.85 (m, 1H), 3.82 – 3.74 (m, 1H), 3.27 –2.96 (m, 4H), 2.33 – 2.18 (m, 1H), 1.81 – 1.49 (m, 5H), 1.29 (d,J = 6.3 Hz, 3H)。 48A   

6-(4-((R)-3-((S)-2-((5-溴-6-側氧基-1,6-二氫嗒𠯤-4-基)氧基)丙氧基)-2-側氧基吡咯啶-1-基)六氫吡啶-1-基)菸鹼甲腈 LCMS (ESI, m/z): 519.10 [M+H]⁺ 48B   

6-(4-((S)-3-((S)-2-((5-溴-6-側氧基-1,6-二氫嗒𠯤-4-基)氧基)丙氧基)-2-側氧基吡咯啶-1-基)六氫吡啶-1-基)菸鹼甲腈 LCMS (ESI, m/z): 519.10 [M+H]⁺ 49A   

5-(((S)-1-(((S)-1-(1-(5-甲基嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)氧基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 497.30 [M+H]⁺ 49B   

5-(((S)-1-(((R)-1-(1-(5-甲基嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)氧基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 497.30 [M+H]⁺ Examples 46-49 Examples 46-49 are based on the -Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl) ⁢(2H)-one and 5 -(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrole (Pyridin-3-yl) oxy) prop-2-yl) oxy)-4-(trifluoromethyl) 𠯤-3( 2H )-one The procedure described in the synthesis (see Examples 20A and 20B) , If necessary, use appropriate building elements and modified reaction conditions (such as reagent ratio, temperature, coupling conditions and reaction time) to synthesize. The relative stereochemistry of the compound is assigned by analogy to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure. Instance number structure analyze data 46A

4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridine) -4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one LCMS (ESI, m/z): 563.10 [M+H] ⁺ ; 1H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.69 (d, J = 0.9 Hz, 2H), 7.92 (s , 1H), 6.48 (br s, 1H), 4.83 (d, J = 12.9 Hz, 1H), 4.57 – 4.45 (m, 1H), 4.20 – 4.00 (m, 1H), 3.86 – 3.78 (m, 2H) , 3.62 – 3.53 (m, 1H), 3.20 – 2.90 (m, 4H), 1.95 – 1.51 (m, 8H), 1.16 (d, J = 6.3 Hz, 3H). 46B

4-bromo-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridine) -4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one LCMS (ESI, m/z): 563.10 [M+H] ⁺ ; 1H NMR (300 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.69 (d, J = 0.9 Hz, 2H), 7.94 (s , 1H), 6.47 (br s, 1H), 4.84 (d, J = 12.9 Hz, 1H), 4.65 – 4.35 (m, 1H), 4.22 – 4.01 (m, 1H), 3.89 – 3.72 (m, 2H) , 3.68 – 3.58 (m, 1H), 3.15 – 2.90 (m, 4H), 2.00 – 1.47 (m, 8H), 1.15 (d, J = 6.3 Hz, 3H). 47A

4-chloro-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one LCMS (ESI, m/z): 517.10 [M+H] ⁺ ; ¹ H NMR(300 MHz, DMSO- d ₆ ) δ 13.22 (s, 1H), 8.70 (s, 2H), 8.21 (s, 1H) , 5.30 – 5.10 (m, 1H), 4.83 (d, J = 13.5 Hz, 2H), 4.21 – 3.90 (m, 3H), 3.72 – 3.61 (m, 1H), 3.25 – 2.98 (m, 4H), 2.27 – 2.06 (m, 1H), 1.72 – 1.48 (m, 5H), 1.29 (d, J = 6.3 Hz, 3H). 47B

4-chloro-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one LCMS (ESI, m/z): 517.10 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ13.22 (s, 1H), 8.70 (s, 2H), 8.23 (s, 1H ), 5.11 – 4.99 (m, 1H), 4.82 (d, J = 13.4 Hz, 2H), 4.17 -3.99 (m, 2H), 3.98 – 3.85 (m, 1H), 3.82 – 3.74 (m, 1H), 3.27 – 2.96 (m, 4H), 2.33 – 2.18 (m, 1H), 1.81 – 1.49 (m, 5H), 1.29 (d, J = 6.3 Hz, 3H). 48A

6-(4-((R)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrota𠯤-4-yl)oxy)propoxy )-2-Pyrrolidine-1-yl)hexahydropyridin-1-yl)nicotinonitrile LCMS (ESI, m/z): 519.10 [M+H] ⁺ 48B

6-(4-((S)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrota𠯤-4-yl)oxy)propoxy )-2-Pyrrolidine-1-yl)hexahydropyridin-1-yl)nicotinonitrile LCMS (ESI, m/z): 519.10 [M+H] ⁺ 49A

5-(((S)-1-(((S)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -Yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 497.30 [M+H] ⁺ 49B

5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -Yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 497.30 [M+H] ⁺

Example 50 : 6-(4-((R)-3-((S)-3 -methoxy- 2-((6- side oxy -5-( trifluoromethyl )-1,6- di ( Hydroxypyridine- 4 -yl ) oxy ) propoxy )-2 -oxopyrrolidin- 1 -yl ) hexahydropyridin- 1 -yl ) nicotinonitrile and 6-(4-((S) -3-((S)-3 -Methoxy- 2-((6 -Pendant oxy -5-( trifluoromethyl )-1,6- dihydrota- 4 -yl ) oxy ) propane (Oxy )-2- side oxypyrrolidin- 1 -yl ) hexahydropyridin- 1 -yl ) nicotine carbonitrile synthesis

Step A To the solution of 3-hydroxy-1-(hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (2.00 g, 9.06 mmol, 1.0 equiv) in DMF (8 mL) was added 6- Chloronicotinonitrile (1.26 g, 9.09 mmol, 1.0 equiv) and K ₂ CO ₃ (2.50 g, 18.1 mmol, 2.0 equiv). The resulting solution was stirred at 80°C for 2 hours, and then quenched by adding water (20 mL). The solution was extracted with 2 × 50 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (60/40) to obtain 1.8 g (69% yield) of white solid 6-(4-(3-hydroxy-2) -Pendant oxypyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile. (ES, m/z): 287.15 [M+H] ⁺ .

Step B Add 6-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (600 mg, 2.10 mmol, 1.0 equiv) at 0°C Add NaH (334 mg, 8.35 mmol, 4.0 equiv, 60% dispersion in mineral oil) to the solution in DMF (5 mL). The solution was stirred at 0°C for 10 min, and then (S)-3-nitrobenzenesulfonate oxiran-2-ylmethyl ester (650 mg, 2.51 mmol, 1.2 equiv) was added. The solution was stirred at 50°C for 25 hours. MeOH (5 mL) was added, and the reaction was stirred at 50 °C for another 2 hours. After concentration, the _{crude product was purified by reverse phase chromatography with water/CH 3} CN (45/55) to obtain 300 mg (39% yield) of white solid 6-(4-(3-((S) (-2-Hydroxy-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotine carbonitrile. (ES, m/z ): 375.25 [M+H] ⁺ .

Step C to 6-(4-(3-((S)-2-hydroxy-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl) Nicotine carbonitrile (120 mg, 0.32 mmol, 1.0 equiv) in DCM (4 mL) was added with 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl) 𠯤-3(2H)-ketone (120 mg, 0.38 mmol, 1.2 equiv) and t-BuOK (72 mg, 0.64 mmol, 2.0 equiv). The resulting solution was stirred for 2 hours, and then concentrated in vacuo. The crude product was applied to a silica gel column and eluted with MeOH/DCM (8/92) to obtain 160 mg (68% yield) of white solid 6-(4-(3-((S)-3-methoxy) Base-2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)oxy)propane (Oxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile. LCMS (ESI, m/z): 657.25 [M+H] ⁺ .

Step D adds 6-(4-(3-((S)-3-methoxy-2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl) Yl)-1,6-dihydrotetrakis-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (160 A solution of mg, 0.244 mmol, 1.00 equiv) in 1.2 ml TFA and trifluoromethanesulfonic acid (5/1) was stirred at 0°C for 10 minutes. The reaction was then quenched by adding water/ice (10 mL). Adjust the pH of the solution to ~7-8 with saturated Na ₂ CO _{3 aqueous solution.} The resulting solution was extracted with 3 × 50 mL DCM. The organic layers were combined and concentrated in vacuo. The crude product was purified by reverse phase chromatography, and the isomeric mixture was separated by chiral prep HPLC: CHIRALPAK IA, 2*25 cm, 5 µm; mobile phase A: MTBE (10 mM NH ₃ -MEOH), mobile phase B : EtOH; Flow rate: 16 mL/min; Gradient: 30% B for 15 min; 220/254 nm to obtain separated compounds. The relative stereochemistry of the compound is specified by analogous to Example 10, based on the PARP7 efficacy of the more active diastereomer, and the X-ray crystal structure similar to Example 10B.

Example 50 Isomer A (50A) : 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl) )-1,6-Dihydropyridin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (46 mg , 35% yield, white solid). LCMS (ESI, m/z): 537.15[M+H] ⁺ ; ¹ HNMR (300 MHz, DMSO-d6) δ 13.21 (s, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.27 (s, 1H), 7.80 (dd, J = 9.1, 2.4 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 5.21 (br, 1H), 4.52 (d , J = 13.4 Hz, 2H), 4.09 – 3.96 (m, 3H), 3.77-3.64 (m, 1H), 3.62-3.47 (m, 2H), 3.26(s,3H), 3.23-3.04 (m, 2H) ), 3.02-2.89 (m, 2H), 2.25 -2.11 (m, 1H), 1.69-1.46 (m, 5H). CHIRALPAK IA-3, 4.6*100 mm 3 µm; mobile phase A: MtBE (0.1% diethylamine): EtOH = 75:25; flow rate: 1 mL/min; retention time: 1.589 min (faster peak).

Example 50 Isomer A (50B) : 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl) )-1,6-Dihydropyridin-4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (54 mg , 41% yield, white solid). LCMS (ESI, m/z): 537.15[M+H] ⁺ , ¹ H NMR (300 MHz, DMSO-d6) δ 13.21 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.29 (s, 1H), 7.80 (dd, J = 9.1, 2.4 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 5.21 (br, 1H), 4.52 ( d, J = 13.3 Hz, 2H), 4.11-3.87 (m, 3H), 3.85-3.75 (m, 1H), 3.64 -3.47 (m, 2H), 3.25 (s,3H), 3.24 -2.87 (m, 4H), 2.27 -2.13 (m, 1H), 1.76 -1.47 (m, 5H). CHIRALPAK IA-3, 4.6*100 mm 3 µm; mobile phase A: MtBE (0.1% diethylamine): EtOH=75:25; flow rate: 1 mL/min; retention time: 1.992 min (slower peak).

5-(((S)-1-甲氧基-3-(((S)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 581.20 [M+H]⁺ 51B   

5-(((S)-1-甲氧基-3-(((R)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 581.20 [M+H]⁺    52A   

5-(((S)-1-甲氧基-3-(((S)-1-(1-(5-甲基嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)氧基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 527.20 [M+H]⁺ 52B   

5-(((S)-1-甲氧基-3-(((R)-1-(1-(5-甲基嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)氧基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 527.15 [M+H]⁺ Examples 51-52 Examples 51-52 are based on 6-(4-((R)-3-((S)-3-methoxy-2-((6- pendant oxy-5-(trifluoromethyl Yl)-1,6-dihydrota (4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile and 6 -(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydrota𠯤- 4-yl)oxy)propoxy)-2-side oxypyrrolidin-1-yl)hexahydropyridin-1-yl)nicotine carbonitrile (see Example 50), as needed It is synthesized using appropriate construction components and modified reaction conditions (such as reagent ratio, temperature, coupling conditions, and reaction time). The relative stereochemistry of the compound is assigned by analogy to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure. Instance number structure analyze data 51A

5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro (Pyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 581.20 [M+H] ⁺ 51B

5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro (Pyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 581.20 [M+H] ⁺ 52A

5-(((S)-1-methoxy-3-(((S)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-side (Oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 527.20 [M+H] ⁺ 52B

5-(((S)-1-methoxy-3-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-side (Oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 527.15 [M+H] ⁺

5-(((S)-1-甲氧基-3-(((R)-1-(1-(5-甲基嘧啶-2-基)六氫吡啶-4-基)-2-側氧基吡咯啶-3-基)氧基)丙-2-基)胺基)-4-(三氟甲基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 526.30 [M+H]⁺ 54   

2-(4-((R)-3-((S)-3-甲氧基-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)-2-側氧基吡咯啶-1-基)六氫吡啶-1-基)噻唑-5-甲腈 LCMS (ESI, m/z): 542.20 [M+H]⁺ ；¹ H NMR (300 MHz, DMSO-d₆ ) δ 12.49 (s, 1H), 7.97 (d,J = 14.5 Hz, 2H), 6.28 (br, 1H), 4.30 (br, 1H), 4.11 - 3.95 (m, 4H), 3.70 - 3.58 (m, 3H), 3.48 (d,J = 5.2 Hz, 3H), 3.27 - 3.22 ( m, 3H),  3.18 – 3.06 (m, 2H), 2.25 (br, 1H), 1.78 – 1.62 (m, 5H)。 Examples 53 and 54 Examples 53 and 54 are based on 6-(4-((S)-3-((S)-3-methoxy-2-((6- pendant oxy-5-(trifluoromethyl Yl)-1,6-dihydrotetrakis-4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile and 6 -(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydrota𠯤- 4-yl) amino) propoxy) -2- side oxypyrrolidin-1-yl) hexahydropyridin-1-yl) nicotine carbonitrile (see Examples 17A and 17B), It can be synthesized using appropriate construction components and modified reaction conditions (such as reagent ratio, temperature, coupling conditions, and reaction time) as needed. Instance number structure analyze data 53

5-(((S)-1-methoxy-3-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-side (Oxypyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one LCMS (ESI, m/z): 526.30 [M+H] ⁺ 54

2-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydrota𠯤 -4-yl)amino)propoxy)-2-side oxypyrrolidin-1-yl)hexahydropyridin-1-yl)thiazole-5-carbonitrile LCMS (ESI, m/z): 542.20 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.49 (s, 1H), 7.97 (d, J = 14.5 Hz, 2H), 6.28 (br, 1H), 4.30 (br, 1H), 4.11-3.95 (m, 4H), 3.70-3.58 (m, 3H), 3.48 (d, J = 5.2 Hz, 3H), 3.27-3.22 (m, 3H ), 3.18 – 3.06 (m, 2H), 2.25 (br, 1H), 1.78 – 1.62 (m, 5H).

Example 55: 6- (4 - (( R) -3 - ((S) -2 - ((5- bromo-6-oxo-1,6-dihydropyridazine 𠯤-yl) oxy) -3 -Methoxypropoxy )-2- side oxypyrrolidin- 1 -yl ) hexahydropyridin- 1 -yl ) nicotinonitrile and 6-(4-((S)-3-(( S)-2-((5- Bromo -6 -oxo -1,6 - dihydrox- 4 -yl ) oxy )-3 -methoxypropoxy )-2 -oxopyrrole l-yl) -piperidine-1-yl) nicotinic-carbonitrile synthesis of

Step A: Add 6-(4-(3-((S)-2-hydroxy-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridine- 1-base) Nicotine carbonitrile (280 mg, 0.75 mmol, 1.0 equiv) in DMF (3 mL) was added with NaH (60 mg, 1.50 mmol, 2.01 equiv, 60% dispersion in mineral oil). The mixture was stirred at 0°C for 10 min, and then 4,5-dibromo-2-(4-methoxybenzyl)papa-3(2H)-one (330 mg, 0.88 mmol, 1.2 equiv) was added, And the resulting solution was stirred at room temperature for 1 hour. The reaction was then quenched with saturated _{aqueous NH 4} Cl (0.5 mL), and the resulting mixture was concentrated. The crude product was purified by a reverse phase column eluted with water/CH ₃ CN (65/45) to obtain 150 mg (30% yield) of a yellow solid 6-(4-(3-((S)- 2-((5-bromo-1-(4-methoxybenzyl)-6-pendant oxy-1,6-dihydrota-4-yl)oxy)-3-methoxypropoxy Yl)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotine carbonitrile. (ES, m/z ): 669.30 [M+H] ⁺ .

Step B converts 6-(4-(3-((S)-2-((5-bromo-1-(4-methoxybenzyl)-6-pendant oxy-1,6-dihydro -4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (150 mg, 0.23 mmol, A solution of 1.0 equiv) in 1:5 TfOH/TFA (1.5 mL) was stirred at room temperature for 15 min. The resulting solution was diluted with water (15 mL), and the pH was adjusted to 7-8 with sodium bicarbonate solution. The solution was extracted with 3 × 50 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by reversed-phase chromatography with water/CH ₃ CN elution, and the isomeric mixture was separated by chiral prep HPLC: chiral ART Cellulose-SB, 2*25 cm, 5 µm; mobile phase A: MTBE (10 mM NH ₃ -MEOH), mobile phase B: EtOH; flow rate: 20 mL/min; gradient: 20% B for 15 min; 220/254 nm. The relative stereochemistry of the compound is assigned by analogy to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure.

Example 55 Isomer A (55A) : 6-(4-((S)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrota 𠯤- 4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotine carbonitrile (31 mg, 25% yield , White solid). LCMS (ESI, m/z): 549.10 [M+H] ⁺ ; 1H NMR (400 MHz, DMSO- d ₆ ) δ 13.13 (s, 1H), 8.47 (s, 1H), 8.11 ( s, 1H), 7.83 (d, J = 9.1 Hz, 1H), 6.96 (d, J = 9.1 Hz, 1H), 5.08 (br, 1H), 4.59-4.48 (m, 2H), 4.12-3.95 (m , 3H), 3.79-3.70 (m, 1H), 3.65-3.54 (m, 2H), 3.29 (s,3H), 3.25-3.06 (m, 2H), 3.04-2.91 (m, 2H), 2.27-2.15 (m, 1H), 1.72-1.46 (m, 5H). Chiral HPLC: Column: Chiral ART Cellulose-SB, 4.6*100 mm, 3 um; Mobile phase: MtBE (0.1% diethylamine): EtOH=80:20; Flow rate: 1 mL/min. Residence time: 3.928 min (faster peak).

Example 55 Isomer A (55B) : 6-(4-((R)-3-((S)-2-((5-bromo-6-oxo-1,6-dihydro- 4-yl)oxy)-3-methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (42 mg, 35% yield , White solid). LCMS (ESI, m/z): 549.15 [M+H] ⁺ ; 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.47 (s, 1H), 8.13 (s , 1H), 7.85 (d, J = 9.2 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 5.08 (br, 1H), 4.57 – 4.49 (m, 2H), 4.14-3.91 (m, 3H), 3.86-3.79 (m, 1H), 3.65-3.53 (m, 2H), 3.29 (s, 3H), 3.25-3.07 (m, 2H), 3.05-2.92 (m, 2H), 2.34-2.19( m, 1H), 1.78 – 1.46 (m, 5H). Chiral HPLC: Column: Chiral ART Cellulose-SB, 4.6*100 mm, 3 µm; Mobile phase: MtBE (0.1% diethylamine): EtOH = 80:20; Flow rate: 1 mL/min. Residence time: 4.384 min (slower peak).

4-溴-5-(((S)-1-甲氧基-3-(((S)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 593.10 [M+H]⁺ 56B   

4-溴-5-(((S)-1-甲氧基-3-(((R)-2-側氧基-1-(1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-4-基)吡咯啶-3-基)氧基)丙-2-基)氧基)嗒𠯤-3(2H)-酮 LCMS (ESI, m/z): 593.10 [M+H]⁺ Example 56 Example 56 is based on 6-(4-((R)-3-((S)-2-((5-bromo-6-pendant oxo-1,6-dihydros )Oxy)-3-methoxypropoxy)-2-side oxypyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile and 6-(4-((S)- 3-((S)-2-((5-Bromo-6-oxo-1,6-dihydrota-4-yl)oxy)-3-methoxypropoxy)-2- The procedure described in the synthesis of pendant oxypyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile (see Example 55), use appropriate construction components and modified reaction conditions (e.g. reagent ratios) as necessary , Temperature, coupling conditions and reaction time) to synthesize. The relative stereochemistry of the compound is assigned by analogy to Example 10, based on the PARP7 efficacy of the more active diastereomer, and similar to Example 10B X-ray crystal structure. Instance number structure analyze data 56A

4-Bromo-5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine-2- (Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one LCMS (ESI, m/z): 593.10 [M+H] ⁺ 56B

4-Bromo-5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine-2- (Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one LCMS (ESI, m/z): 593.10 [M+H] ⁺

Example 57 : 5-(((S)-1-(((R)-1-((3R,4R)-3 -hydroxy- 1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexa hydrogen pyridin-4-yl) -2-oxo pyrrolidin-3-yl) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one Synthesis

Step A : Add 2 -Chloro-5-(trifluoromethyl)pyrimidine (825 mg, 4.52 mmol, 1.0 equiv) and K ₂ CO ₃ (940 mg, 6.80 mmol, 1.5 equiv). The resulting solution was stirred at 50°C for 1 hour, and then quenched by the addition of water (15 mL). The solid was collected by filtration to obtain 1.6 g (97% yield) of ((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro as a white solid (Pyridin-4-yl)carbamic acid tert-butyl ester. (ESI, m/z ): 363.10 [M+H] ⁺ .

Step B: ((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)aminocarboxylate (1.60 g, A solution of 4.42 mmol, 1.0 equiv) in 4M HCl (30 mL) in 1,4-dioxane was stirred at 40°C for 1 hour. The resulting mixture was concentrated in vacuo to obtain 1.1 g (95% yield) of (3R,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexan as a white solid Hydropyridine-3-ol hydrochloride. (ESI, m/z ): 263.05 [M+H] ⁺ .

Step C To (3R, 4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-ol hydrochloride (980 mg, 3.74 mmol, 1.0 equiv ) Add imidazole (1.27 g, 18.7 mmol, 5.0 equiv) and tert-butylchlorodimethylsilane (1.69 g, 11.2 mmol, 3.0 equiv) to the solution in CH _{3 CN (30 mL).} The resulting solution was stirred at 60°C for 30 hours. After filtration, the filtrate was concentrated in vacuo, and the crude product was applied to a silica gel column eluted with MeOH/DCM (3:97) to obtain 1.3 g (92% yield) of a yellow oil (3R, 4R) )-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine. (ESI, m/z ): 377.4 [M+H] ⁺ .

Step D: (3R, 4R)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4- Amine (1.28 g, 3.40 mmol, 1.0 equiv) in DCM (20 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane) Cyclo-4-yl)acetaldehyde (1.88 g, 11.9 mmol, 3.5 equiv) and AcOH (408 mg, 6.79 mmol, 2.0 equiv). The resulting solution was stirred for 1 hour. STAB (2.16 g, 10.2 mmol, 3.0 equiv) was added, and the solution was stirred for another 4 hours. The reaction was quenched by adding saturated aqueous NaHCO _{3 solution.} The aqueous layer was extracted with 2×50 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (35/65) to obtain 680 mg (43% yield) of (R)-1-((3R,4R) as a white solid )-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrole Pyridin-2-one. (ESI, m/z ): 461.20 [M+H] ⁺ .

Step E To (R)-1-((3R,4R)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidine at 0℃ -2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one (670 mg, 1.46 mmol, 1.00 equiv) in DMF (7 mL) was added with NaH (117 mg, 2.93 mmol, 2.01 equiv, 60% dispersion in mineral oil). The resulting solution was stirred for 10 min, and then (S)-4-methyl-1,2,3-oxathiazolidine-3-acetic acid tert-butyl 2,2-dioxide (518 mg, 2.18 mmol , 1.5 equiv), and maintain the solution at the same temperature for 4 hours. Then by addition of saturated NH ₄ Cl solution to quench the reaction. The solution was extracted with 2 × 50 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (3/2) to obtain 300 mg (33% yield) of ((S)-1-(((R )-1-((3R,4R)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester. (ESI, m/z ): 618.30 [M+H] ⁺ .

Step F will ((S)-1-(((R)-1-((3R,4R)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(三(Fluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)carbamate (290 mg , 0.47 mmol, 1.0 equiv) in 4N HCl (20 mL) in 1,4-dioxane was stirred for 15 hours. The resulting mixture was concentrated to obtain 240 mg of white solid (R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-3-hydroxy-1-(5-( Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride, which was used without further purification. (ESI, m/z ): 404.15 [M+H] ⁺ .

Step G to (R)-3-((S)-2-aminopropoxy)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidine-2 -Yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (230 mg, 0.57 mmol, 1.0 equiv) in EtOH (4 mL) was added 5-chloro-2-(4- Methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one (181 mg, 0.57 mmol, 1.0 equiv) and triethylamine (173 mg, 1.71 mmol, 3.0 equiv). The resulting solution was stirred at 60°C for 1 hour. After completion, the crude product was applied to a _{reversed-phase column eluted with water/CH 3} CN (45/55) to obtain 185 mg (47% yield) of white solid 5-((((S)-1) -(((R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxo (Pyrrolidin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one . (ESI, m/z ): 686.25 [M+H] ⁺ .

Step H convert 5-(((S)-1-(((R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)) (Hydropyridin-4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoro A solution of methyl) 𠯤-3(2H)-one (185 mg, 0.270 mmol, 1.0 equiv) in TFA (1.5 mL) and TfOH (0.3 mL) was stirred for 1 hour. The reaction was quenched by adding ice water (2 mL). Adjust the pH to ~7-8 with saturated Na ₂ CO _{3 aqueous solution.} The resulting solution was extracted with 2 × 50 mL DCM. The organic layers were combined and concentrated. The crude product was purified by reverse phase chromatography eluted with water/CH ₃ CN (45/55) to obtain 89 mg (59% yield) of 5-(((S)-1-((() R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine- 3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one. (ESI, m/z ): 566.15 [M+H] ⁺ ; 1H NMR (300 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.69 (d, J = 0.9 Hz, 2H), 7.94 (s, 1H), 6.39-6.29 (m, 1H), 5.28 (d, J = 5.3 Hz, 1H), 4.91-4.80 (m, 1H), 4.72 (d, J = 13.4 Hz, 1H), 4.21-4.07 (m , 2H), 3.84-3.73 (m, 2H), 3.63-3.49 (m, 2H), 3.29-3.22 (m, 1H), 3.17-3.07 (m, 1H), 3.02-2.89 (m, 1H), 2.84 -2.70 (m,1H), 2.31-2.16 (m, 1H), 1.83-1.68 (m, 1H), 1.65-1.48 (m, 2H), 1.16 (d, J = 6.4 Hz, 3H).

Example 58: 5 - (((S ) -1 - (((R) -1 - ((3S, 4S) -3- hydroxy-l- (5- (trifluoromethyl) pyrimidin-2-yl) six hydrogen pyridin-4-yl) -2-oxo pyrrolidin-3-yl) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one Synthesis

Step A : Add K to a solution of ((3S,4S)-3-hydroxyhexahydropyridin-4-yl)aminocarboxylate (1.00 g, 4.62 mmol, 1.0 equiv) in DMF (5 mL) ₂ CO ₃ (0.96 g, 6.95 mmol, 1.5 equiv) and 2-chloro-5-(trifluoromethyl)pyrimidine (0.85 g, 4.66 mmol, 1.0 equiv). The resulting solution was stirred at 50°C for 1 hour. The reaction mixture was quenched by adding 10 mL of water, and the solid was collected by filtration to obtain 1.45 g (87% yield) of ((3S,4S)-3-hydroxy-1-(5-(三)) as a white solid Fluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)carbamic acid tert-butyl ester. LCMS (ESI, m/z): 363.10 [M+H] ⁺ .

Step B ((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)aminocarboxylate (1.45 g, A solution of 4.00 mmol, 1.0 equiv) in 4N HCl (30 mL) in 1,4-dioxane was stirred at 40°C for 2 hours. The resulting mixture was concentrated to obtain 1.0 g (95% yield) of (3S,4S)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- as a yellow solid 3-alcohol hydrochloride. LCMS (ESI, m/z): 263.05 [M+H] ⁺ .

Step C To (3S, 4S)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-ol hydrochloride (1.19 g, 3.98 mmol, 1.0 equiv ) Add tertiary butyldimethylsilyl chloride (2.36 g, 15.7 mmol, 3.93 equiv) and imidazole (1.77 g, 26.0 mmol, 6.5 equiv) to the solution in CH _{3 CN (40 mL).} The resulting solution was stirred at 60°C overnight. After filtration, the filtrate was concentrated in vacuo, and the crude product was applied to a silica gel column eluted with chloroform/methanol (10/1) to obtain 1.20 g (80% yield) of a white solid (3S, 4S) )-3-((tert-butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)hexahydropyridine-4-amine. LCMS (ESI, m/z): 377.10 [M+H] ⁺

Step D to (3S,4S)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-methylpyrimidin-2-yl)hexahydropyridine-4-amine (1.40 g , 3.72 mmol, 1.0 equiv) in DCM (20 mL), add (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane-4- Base) acetaldehyde (1.88 g, 11.9 mmol, 3.2 equiv) and AcOH (446 mg, 7.44 mmol, 2.0 equiv). After stirring for 15 min, STAB (2.36 g, 11.2 mmol, 3.0 equiv) was added, and the solution was stirred for another 5 hours. The reaction was quenched by adding 20 mL saturated aqueous NaHCO ₃ solution and extracted with 3×50 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (3/2) to obtain 470 mg (27% yield) of (R)-1-((3S,4S) as a yellow solid )-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrole Pyridin-2-one. LCMS (ESI, m/z): 461.20 [M+H] ⁺ .

Step E To (R)-1-((3S,4S)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidine at 0℃ -2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one (465 mg, 1.01 mmol, 1.0 equiv) in DMF (5 mL) with NaH (121 mg, 3.03 mmol, 3.0 equiv, 60%). The reaction mixture was stirred for 10 min, and then (S)-4-methyl-1,2,3-oxathiazolidine-3-acetic acid tert-butyl 2,2-dioxide (287 mg, 1.21 mmol , 1.2 equiv) in DMF (2 mL). The resulting solution was stirred at 0°C for 2 hours. The reaction was quenched by adding water (10 mL). The resulting solution was extracted with 2 × 20 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (3/2) to obtain 480 mg (77% yield) of ((S)-1-(((R )-1-((3S,4S)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester. LCMS (ESI, m/z): 618.35 [M+H] ⁺ .

Step F ((S)-1-(((R)-1-((3S,4S)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(三(Fluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)aminocarbamate (480 mg , 0.78 mmol, 1.0 equiv) in 4M HCl (10 mL, 4 M) in 1,4-dioxane was stirred at room temperature for 1 hour. The resulting mixture was concentrated in vacuo to obtain 278 mg (81% yield) of (R)-3-((S)-2-aminopropoxy)-1-((3S,4S)- as a white solid 3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride. (ESI, m/z ): 461.25 [M+H] ⁺ .

Step G to (R) -3 - ((S ) -2- amino-propoxy) -1 - ((3S, 4S ) -3- hydroxy-l- (5- (trifluoromethyl) pyrimidin - 2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (270 mg, 0.61 mmol, 1.0 equiv) in EtOH (8 mL), add 5-chloro-2-(4 -Methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one (293 mg, 0.92 mmol, 1.5 equiv) and triethylamine (621 mg, 6.14 mmol, 10.0 equiv). The resulting solution was stirred at 60°C for 3 hours and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (7/3) to obtain 280 mg (67% yield) of 5-(((S)-1-() as a yellow solid ((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrole (Pyridin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)taka-3(2H)-one. LCMS (ESI, m/z): 686.20 [M+H] ⁺ .

Step H converts 5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)) (Hydropyridin-4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoro A solution of methyl) 𠯤-3(2H)-one (270 mg, 0.39 mmol, 1.0 equiv) in TfOH/TFA=1:10 (3 mL) was stirred at 0°C for 2 hours. The reaction was quenched by adding water (5 mL), and the pH was adjusted to 7-8 with aqueous sodium bicarbonate. The resulting solution was extracted with 3 × 20 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by reversed-phase chromatography eluted with water/CH ₃ CN (1/1) to obtain 120 mg (54% yield) of 5-(((S)-1-((() R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine- 3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one. LCMS (ESI, m/z): 566.20 [M+H] ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ 12.46 (s, 1H), 8.70 (s, 2H), 7.95 (s, 1H), 6.35-6.34 (m, 1H), 5.26 (d, J = 5.0 Hz, 1H), 4.91-4.83 (m, 1H), 4.80-4.75 (m, 1H), 4.28-4.10 (m, 2H), 3.80- 3.91(m, 2H), 3.63-3.58(m, 1H), 3.55 -3.40 (m, 1H), 3.31-3.25(m, 1H), 3.22-3.12 (m, 1H), 3.06-2.95 (m, 1H) ), 2.81-2.76 (m, 1H), 2.33-2.20 (m, 1H), 1.78-1.66 (m, 1H), 1.64-1.51(m, 2H), 1.17 (d, J = 6.4 Hz, 3H).

Example 59: 5 - (((S ) -1 - (((R) -1 - ((3S, 4R) -3- hydroxy-l- (5- (trifluoromethyl) pyrimidin-2-yl) six hydrogen pyridin-4-yl) -2-oxo pyrrolidin-3-yl) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one Synthesis

Step A : Add 2 -Chloro-5-(trifluoromethyl)pyrimidine (1.68 g, 9.2 mmol, 1.00 equiv) and K ₂ CO ₃ (2.56 g, 18.5 mmol, 2.0 equiv). The resulting solution was stirred at 50°C for 1 hour and then diluted with water (10 mL). The solid was collected by filtration to obtain 1.37 g (39% yield) of ((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro as a white solid (Pyridin-4-yl)carbamic acid tert-butyl ester. LCMS (ESI, m/z): 363.10 [M+H] ⁺ .

Step B ((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)aminocarboxylate (1.28 g, A solution of 3.53 mmol, 1.0 equiv) in 4M HCl (6 mL) in dioxane was stirred for 2 hours. The resulting mixture was concentrated in vacuo to obtain 1.0 g (95% yield) of (3S,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexan as a yellow solid Hydropyridine-3-ol hydrochloride. LCMS (ESI, m/z): 263.05 [M+H] ⁺ .

Step C To (3S, 4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-3-ol hydrochloride (2.60 g, 9.92 mmol, 1.0 equiv ) Add tertiary butyl dimethylsilyl chloride (11.95 g, 79.35 mmol, 8.0 equiv) and imidazole (5.40 g, 79.4 mmol, 8.0 equiv) to the solution in CH _{3 CN (20 mL).} The resulting solution was stirred at 60°C for 4 hours and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with chloroform/methanol (9/1) to produce 3.40 g (88% yield) of (3S,4R)-3-((tertiary butyl) as a yellow solid Dimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine. LCMS (ESI, m/z): 377.10 [M+H] ⁺ .

Step D: To (3S,4R)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4- Amine (3.20 g, 8.50 mmol, 1.0 equiv) in DCM (30 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane) Cyclo-4-yl)acetaldehyde (1.24 g, 7.82 mmol, 0.9 equiv) and AcOH (1.53 g, 25.5 mmol, 3.0 equiv). The resulting solution was stirred for 15 min, and then STAB (14.0 g, 66.0 mmol, 3.0 equiv) was added. After 2 hours, the reaction was quenched by adding 20 mL of saturated aqueous NaHCO _{3 solution.} The solution was extracted with 3 × 100 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (3/1) to obtain 0.93 g (24% yield) of yellow solid (R)-1-((3S,4R)- 3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidine- 2-ketone. LCMS (ESI, m/z): 461.20 [M+H] ⁺ .

Step E is a 10 min process at 0℃ to (R)-1-((3S,4R)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(三(Fluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one (920 mg, 2.0 mmol, 1.0 equiv) in DMF (8 mL) is slowly added NaH (239 mg, 5.99 mmol, 3.0 equiv, 60% dispersion in mineral oil). Then (S)-4-methyl-1,2,3-oxathiazolidine-3-acetic acid tert-butyl 2,2-dioxide (568 mg, 2.40 mmol, 1.2 equiv) was added, and the resulting The solution was stirred at 0°C for 2 hours. The reaction was quenched by adding water (10 mL) and extracted with 2×30 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (3/2) to obtain 767 mg (62% yield) of ((S)-1-(((R )-1-((3S,4R)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester. LCMS (ESI, m/z): 618.35 [M+H] ⁺ .

Step F will ((S)-1-(((R)-1-((3S,4R)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(三(Fluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)carbamate (790 mg , 1.28 mmol, 1.0 equiv) in 4M HCl (10 mL) in dioxane was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to obtain 600 mg (96% yield) of (R)-3-((S)-2-aminopropoxy)-1-((3S,4R)-3 as a white solid -Hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride. (ESI, m/z ): 461.25 [M+H] ⁺ .

Step G To (R)-3-((S)-2-aminopropoxy)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidine-2 -Yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (650 mg, 1.6 mmol, 1.0 equiv) in ethanol (8 mL) was added 5-chloro-2-(4- Methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one (616 mg, 1.93 mmol, 1.2 equiv) and triethylamine (1.04 g mg, 8.06 mmol, 5.0 equiv). The resulting solution was stirred at 60°C for 4 hours and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (10/1) to obtain 550 mg (50% yield) of 5-(((S)-1-() as a yellow solid ((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrole (Pyridin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)taka-3(2H)-one. LCMS (ESI, m/z): 686.20 [M+H] ⁺ .

Step H will 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyridin-2-yl)hexa (Hydropyridin-4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoro A solution of (methyl)pah-3(2H)-ketone (550 mg, 0.80 mmol, 1.0 equiv) in TfOH/TFA (3 mL, 1:10) was stirred at room temperature for 2 hours and then by adding water (5 mL) Quench. Adjust the pH to 7-8 with sodium bicarbonate. The resulting solution was extracted with 3 × 20 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by reversed-phase chromatography eluted with water/CH ₃ CN (3/2) to obtain 189 mg (42% yield) of 5-(((S)-1-((() R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine- 3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one. LCMS (ESI, m/z): 566.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.47 (s, 1H), 8.65 (s, 2H), 7.96 (s, 1H) , 6.38 (br, 1H), 5.06 (d, J = 5.1 Hz, 1H), 4.93-4.78(m, 2H), 4.21-4.09 (m, 2H), 4.02-3.94(m, 1H), 3.92-3.81 (m, 2H), 3.62-3.56 (m, 2H), 3.26 – 3.10 (m, 2H), 3.04 (t, J = 12.6 Hz, 1H), 2.29 – 2.18 (m, 1H), 2.12 – 1.99 (m , 1H), 1.83 – 1.69 (m, 1H), 1.53 (d, J = 12.3 Hz, 1H), 1.18 (d, J = 6.4 Hz, 3H).

Example 60 : 5-(((S)-1-(((R)-1-((3R,4S)-3 -hydroxy- 1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexa hydrogen pyridin-4-yl) -2-oxo pyrrolidin-3-yl) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2 H) - Synthesis of ketones

Step A : Add K to the solution of ((3R,4S)-3-hydroxyhexahydropyridin-4-yl)aminocarboxylate (1.02 g, 4.71 mmol, 1.0 equiv) in DMF (6 mL) ₂ CO ₃ (980 mg, 7.2 mmol, 1.5 equiv) and 2-chloro-5-(trifluoromethyl)pyrimidine (863 mg, 4.73 mmol, 1.0 equiv). The resulting solution was stirred at 60°C for 2 hours, and then quenched by adding water (20 mL). The solid was collected by filtration to obtain 1.59 g (93% yield) of ((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro as an off-white solid (Pyridin-4-yl)carbamic acid tert-butyl ester. LCMS (ESI, m/z): 363.10 [M+H] ⁺ .

Step B to ((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)aminocarboxylate (1.59 g, 4.39 mmol, 1.0 equiv) in dioxane (50 mL) add 4N HCl in dioxane (30 mL). The resulting solution was stirred for 5 hours and then concentrated to obtain 1.43 g (97% yield) of (3R,4S)-4-amino-1-(5-(trifluoromethyl)pyrimidine-2- Yl)hexahydropyridine-3-ol hydrochloride, which was used without further purification. LCMS (ESI, m/z): 263.10 [M+H] ⁺ .

Step C To (3R, 4S)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-ol hydrochloride (1.43 g, 4.26 mmol, 1.0 equiv ) Add imidazole (2.20 g, 32.3 mmol, 7.6 equiv) and tert-butylchlorodimethylsilane (4.05 g, 26.9 mmol, 6.3 equiv) to the solution in CH _{3 CN (30 mL).} The resulting solution was stirred at 60°C for 15 hours and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with dichloromethane/methanol (19/1) to obtain 1.74 g (98% yield) of orange oil (3R,4S)-3-((third Butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine. LCMS (ESI, m/z): 377.20 [M+H] ⁺ .

Step D To (3R, 4S)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4- Amine (1.74 g, 4.16 mmol, 1.0 equiv) in DCM (50 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane) Cyclo-4-yl)acetaldehyde (3.71 g, 23.5 mmol, 5.6 equiv) and AcOH (0.57 g, 9.6 mmol, 2.3 equiv). The resulting solution was stirred for 1 hour, and then STAB (3.04 g, 14.3 mmol, 3.5 equiv) was added, and the mixture was stirred for another 3 hours. The reaction was quenched by adding 50 mL of saturated aqueous sodium bicarbonate solution. The resulting solution was extracted with 3 × 60 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (2/1) to obtain 1.16 g (56% yield) of (R)-1-((3R,4S) as an off-white solid )-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrole Pyridin-2-one. LCMS (ESI, m/z): 461.20 [M+H] ⁺ .

Step E To (R)-1-((3R,4S)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidine at 0℃ -2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one (1.12 g, 2.43 mmol, 1.0 equiv) in DMF (10 mL) with NaH (437 mg, 11.0 mmol, 4.5 equiv, 60% dispersion in mineral oil). The resulting solution was stirred for 30 min, and then (S)-4-methyl-1,2,3-oxathiazolidine-3-acetic acid tert-butyl 2,2-dioxide (700 mg, 3 mmol , 1.2 equiv) in DMF (2 mL). The reaction mixture was stirred for 13 hours and then quenched by the addition of ice water (10 mL). Adjust the pH to ~6-7 with 2N HCl. The resulting solution was extracted with 3 × 60 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (1/2) to obtain 790 mg (52% yield) of light yellow solid ((S)-1-((( R)-1-((3R,4S)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine -4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)carbamic acid tert-butyl ester. LCMS (ESI, m/z): 618.35 [M+H] ⁺ .

Step F ((S)-1-(((R)-1-((3R,4S)-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(三(Fluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)aminocarbamate (790 mg , 1.28 mmol, 1.0 equiv) in 4N HCl (20 mL) in dioxane was stirred at room temperature for 1.5 days. The resulting mixture was concentrated in vacuo to obtain 600 mg of (R)-3-((S)-2-aminopropoxy)-1-((3R,4S)-3-hydroxy-1-( 5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride, which was used without further purification. LCMS (ESI, m/z): 404.20 [M+H] ⁺ .

Step G to (R)-3-((S)-2-aminopropoxy)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidine-2 -Yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (593 mg, 1.35 mmol, 1.0 equiv) in CH ₃ CN (15 mL) was added diisopropylethylamine ( 750 mg, 5.8 mmol, 4.3 equiv ) and 5-chloro-2- (4-methoxybenzyl) -4- (trifluoromethyl) despair 𠯤 -3 (2 H) - one (452 mg, 1.42 mmol , 1.1 equiv). The resulting solution was stirred at 60°C for 7 hours, and then quenched by the addition of water (20 mL). The resulting solution was extracted with 2 × 30 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a _{reversed-phase column eluted with water/CH 3} CN (1/3) to obtain 706 mg (64% yield) of an off-white solid 5-(((S)-1-(( (R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine -3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)dash-3( 2H )-one. LCMS (ESI, m/z): 686.10 [M+H] ⁺ .

Step H convert 5-(((S)-1-(((R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)) (Hydropyridin-4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoro A solution of methyl) 𠯤-3(2 H )-ketone (706 mg, 1.03 mmol, 1.0 equiv) in TFA/TfOH (4.5 mL, 10:1) was stirred at 0°C for 1 hour and then added Quench with ice water (10 mL). The pH was adjusted to 7 with saturated aqueous NaHCO _{3 solution.} The resulting solution was extracted with 3 × 30 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography eluted with water/CH ₃ CN (2/1) to obtain 254 mg (43% yield) of 5-(((S)-1-(() (R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine -3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)taka-3( 2H )-one. LCMS (ESI, m/z): 566.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.45 (s, 1H), 8.65 (s, 2H), 7.95 (s, 1H) , 6.39 – 6.27 (m, 1H), 5.02 (d, J = 5.1 Hz, 1H), 4.89 – 4.75 (m, 2H), 4.22 – 4.15 (m, 1H), 4.11 (t, J = 7.6 Hz, 1H ), 4.08 – 3.96 (m, 1H), 3.91 (br, 1H), 3.83 (dd, J = 10.0, 6.5 Hz, 1H), 3.61 (dd, J = 10.0, 4.7 Hz, 1H), 3.44 – 3.36 ( m, 1H), 3.35 – 3.26 (m, 1H), 3.13 (d, J = 13.5 Hz, 1H), 3.09 – 2.99 (m, 1H), 2.30 – 2.18 (m, 1H), 2.12 – 1.99 (m, 1H), 1.77 – 1.65 (m, 1H), 1.52 – 1.42 (m, 1H), 1.18 (d, J = 6.5 Hz, 3H).

Example 61 : (S)-N-((R)-2- Pendant oxy- 1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl ) pyrrolidine 3-yl) -2 - ((6-oxo-5- (trifluoromethyl) -1,6-dihydropyridazine 𠯤 4-yl) amino) propan synthesis of Amides.

Step A : Add (2R)-2-[(tertiary butoxycarbonyl)amino]-4-(methylthio)butanoic acid (2.65 g, 10.6 mmol, 1.0 equiv) in DMF (20 mL) Add 1-[5-(trifluoromethyl)pyrimidin-2-yl]hexahydropyridine-4-amine hydrochloride (3.00 g, 10.6 mmol, 1.00 equiv), HATU (4.44 g, 11.7 mmol, 1.1 equiv) and diisopropylethylamine (4.11 g, 31.8 mmol, 3.0 equiv). The resulting solution was stirred for 1 hour and then quenched by adding water (20 mL) and extracted with 3×20 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1/1) to obtain 3.9 g (77% yield) of (R)-(4-(methylthio)- 1-Pendant oxy-1-((1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)amino)but-2-yl)aminocarboxylic acid ester. LCMS (ESI, m/z): 478.20 [M+H] ⁺ .

Step B to (R)-(4-(methylthio)-1-oxo-1-((1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl )Amino)but-2-yl)carbamic acid tert-butyl ester (3.87 g, 8.10 mmol, 1.0 equiv) in DMF (50 mL) with methyl iodide (1.73 g, 12.2 mmol, 1.5 equiv) . The resulting solution was stirred at 30°C overnight and then concentrated in vacuo to obtain 4.7 g (94% yield) of (R)-(3-((tertiary butoxycarbonyl)amino)- as a yellow oil 4-Pendant oxy-4-((1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)amino)butyl)dimethyl iodide. LCMS (ESI, m/z): 492.23 [M] ⁺ .

Step C to (R)-(3-((third butoxycarbonyl)amino)-4- pendant oxy-4-((1-(5-(trifluoromethyl)pyrimidin-2-yl) Hexahydropyridin-4-yl)amino)butyl)dimethyl iodide (4.7 g, 7.6 mmol, 1.0 equiv) in DMF (100 mL) was added with sodium hydride (970 mg, 40.4 mmol, 5.3 equiv, 60% dispersion in mineral oil). The resulting solution was stirred at 30°C overnight and then quenched by adding 100 mL water and extracted with 3×100 mL DCM. The organic layers were combined, washed with water, dried, and concentrated under vacuum. The crude product was recrystallized from PE: EtOAc (10:1) to obtain 2 g (61% yield) of (R)-(2-oxo-1-(1-(5-(trifluoro)) as a white solid (Methyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)carbamate. LCMS (ESI, m/z): 430.20 [M+H] ⁺ .

Step D converts (R)-(2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)amine A solution of tert-butyl carboxylate (2.00 g, 4.66 mmol, 1.00 equiv) in 4N HCl (10 mL) in dioxane was stirred for 2 hours and then concentrated in vacuo to obtain 1.5 g (98% yield ) (R)-3-amino-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one salt as a light yellow solid Acid salt. LCMS (ESI, m/z): 330.15 [M+H] ⁺ .

Step E To (1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4-yl)-L-alanine ( 1.4 g, 8 equiv) Add (R)-3-amino-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- to a solution in DMF (20 mL) 4-yl)pyrrolidin-2-one hydrochloride (155 mg, 1.0 equiv), HATU (179 mg, 1 equiv) and diisopropylethylamine (243 mg). After 2 hours, the reaction was quenched by adding 100 mL water and extracted with 3×100 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase chromatography eluted with water/CH ₃ CN (2/3) to obtain 220 mg (66% yield) of (S)-2-((1-(4- (Methoxybenzyl)-6-Pendant Oxygen-5-(Trifluoromethyl)-1,6-Dihydrotetrafluoromethyl-4-yl)amino)-N-((R)-2-Pendant Oxygen -1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)propanamide. LC-MS (ESI, m/z): 683.25 [M+H] ⁺ .

Step F to (S)-2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4-yl )Amino)-N-((R)-2-Pendant oxy-1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine-3 -Base) propanamide (210 mg, 0.31 mmol, 1.0 equiv) in TFA (2.7 mL) was added TfOH (0.3 mL). The mixture was stirred for 2 hours, and then 50 mL of water was added. The pH was adjusted to 7 with saturated _{aqueous Na 2} CO _{3 solution.} The resulting solution was extracted with 3 × 100 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase chromatography eluted with water/CH ₃ CN (1/1) to obtain 81 mg (46% yield) of (S)-N-((R)-2- Pendant oxy-1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)-2-((6-Pendant oxy- 5-(Trifluoromethyl)-1,6-dihydrotetrakis-4-yl)amino)propanamide. LCMS (ESI, m/z): 563.10 [M+H] ⁺ . 1H NMR (300 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.70 (s, 2H), 8.59 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 6.71 (br, 1H) , 4.93 – 4.69 (m, 2H), 4.53 – 4.31 (m, 2H), 4.09 (br, 1H), 3.30 – 3.24 (m, 1H), 3.24 – 3.11 (m, 1H), 3.11 – 2.94 (m, 2H), 2.36 – 2.18 (m, 1H), 1.82 – 1.47 (m, 5H), 1.37 (d, J = 6.7 Hz, 3H).

Example 62 : 5-(((S)-1-(((R)-2 -oxo- 1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridine -4 - yl) pyrrolidin-3-yl) oxy) -3 - ((2,2,2-trifluoroethyl) amino) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one synthesis of.

Step A to (R)-3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one (1.30 g, 3.94 mmol, 1.0 equiv) in DMF (40 mL), add NaH (0.47 g, 11.8 mmol, 3 equiv, 60% dispersion in mineral oil) and (S)-2,2-dimethyl-4 -((Tosyloxy)methyl)oxazolidine-3-tert-butyl acetate (6.07 g, 15.7 mmol, 4 equiv). The mixture was stirred at 40°C for 7 hours. The reaction was quenched by adding 40 mL of water. After extraction with ethyl acetate, drying the organics over sodium sulfate and filtering, the resulting mixture was concentrated and applied to a silica gel column eluted with ethyl acetate/petroleum ether (34/66) to obtain a white solid (R)- 2,2-Dimethyl-4-((((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl )Pyrrolidin-3-yl)oxy)methyl)oxazolidine-3-acetic acid tert-butyl ester (1.12 g, 47% yield). LCMS (ESI, m/z): 544.30 [M+H] ⁺ .

Step B will (R)-2,2-dimethyl-4-((((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl) Hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)methyl)oxazolidine-3-acetic acid tert-butyl ester (1.12 g, 2.06 mmol, 1.0 equiv) in 1,4-dioxane The solution in (10 mL) was treated with 4N HCl (5 mL) in dioxane. The resulting solution was stirred for 3 hours and concentrated to obtain (R)-3-((S)-2-amino-3-hydroxypropoxy)-1-(1-(5-(trifluoromethyl) as a yellow oil (Yl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrochloride (600 mg, 65% yield). LCMS (ESI, m/z): 404.20 [M+H] ⁺ .

Step C to (R)-3-((S)-2-amino-3-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine -4-yl)pyrrolidin-2-one hydrochloride (420 mg, 0.96 mmol, 1.0 equiv) in i-PrOH (45 mL), add 5-chloro-2-(4-methoxybenzyl) Glycine)-4-(trifluoromethyl)pado-3(2H)-one (304 mg, 0.96 mmol, 1 equiv) and diisopropylethylamine (987 mg, 7.64 mmol, 8 equiv). The resulting solution was stirred at 80°C for 3 hours and then diluted with 150 mL of ethyl acetate. The mixture was washed with 3×50 mL of water and then dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column eluted with ethyl acetate to obtain a yellow oily 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1- (1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-2-(4 -Methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one (440 mg, 60% yield). LCMS (ESI, m/z): 686.25 [M+H] ⁺ .

Step D to 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa (Hydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)- 3(2H)-ketone (775 mg, 1.13 mmol, 1.0 equiv) in DCM (30 mL) was added DMAP (27 mg, 0.23 mmol, 0.2 equiv), triethylamine (343 mg, 3.39 mmol, 3.0 equiv) and 4-toluenesulfonyl chloride (430 mg, 2.3 mmol, 2 equiv). The resulting solution was stirred overnight and then concentrated and applied to a silica gel column eluted with ethyl acetate/petroleum ether (71/29) to obtain a yellow oily (R)-4-toluenesulfonic acid 2-((1 -(4-Methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)-3-(((R) -2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propyl ester (330 mg, 30% yield). LCMS (ESI, m/z): 840.25 [M+H] ⁺ .

Step E To (R)-4-toluenesulfonic acid 2-((1-(4-methoxybenzyl)-6-oxo-5-(trifluoromethyl)-1,6-dihydro 𠯤-4-yl)amino)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4- (Pyrrolidin-3-yl)oxy)propyl ester (330 mg, 0.39 mmol, 1.0 equiv) in DMF (5 mL) with sodium azide (38 mg, 0.59 mmol, 1.5 equiv) . The solution was stirred at 80°C for 1 hour and then quenched by adding 25 mL of water. The mixture was extracted with 3 × 50 mL ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and concentrated to obtain 5-(((2S)-1-azido-3-((2-oxo-1-(1-(5-() (Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl) -4-(Trifluoromethyl)Pak-3(2H)-one (330 mg, 71% yield). LCMS (ESI, m/z): 711.20 [M+H] ⁺ .

Step F to 5-(((2S)-1-azido-3-((2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine -4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)da 𠯤-3( To a solution of 2H)-ketone (330 mg, 0.46 mmol, 1.0 equiv, 60%) in THF (5 mL) was added triphenylphosphine (182 mg, 0.70 mmol, 1.5 equiv) and water (0.5 mL). The solution was stirred at 60°C for 1.5 hours, concentrated, and applied to a silica gel column eluted with DCM/methanol (87/13) to obtain 5-(((2S)-1-amino- 3-((2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan- 2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pado-3(2H)-one (186 mg, 92% yield). LCMS (ESI, m/z): 685.30 [M+H] ⁺ .

Step G is to 5-(((2S)-1-amino-3-((2-side oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pha 𠯤-3(2H )-Ketone (100 mg, 0.15 mmol, 1.00 equiv) in dichloroethane (8 mL) was added 2,2,2-trifluoroacetaldehyde (57 mg, 0.44 mmol, 3 equiv), Ti( Oi-Pr) ₄ (41 mg, 0.15 mmol, 1.0 equiv), AcOH (8 mg, 0.15 mmol, 1 equiv) and NaBH ₃ CN (18 mg, 0.29 mmol, 2 equiv). The resulting solution was stirred at 70°C for 1.5 hours and then diluted with 50 mL ethyl acetate and washed with 3×20 ml water. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a silica gel column eluted with ethyl acetate/petroleum ether (91/9) to obtain 2-(4-methoxybenzyl)-5-(((S)- 1-(((R)-2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy Yl)-3-((2,2,2-trifluoroethyl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one (67 mg, 56% yield). LCMS (ESI, m/z): 767.25 [M+H] ⁺ .

Step H adds 2-(4-methoxybenzyl)-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl) )Pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)propan-2-yl) Amino)-4-(trifluoromethyl)- 3(2H)-one (60 mg, 0.08 mmol, 1.0 equiv) in TFA (1 mL) was added TfOH (0.1 mL), and The mixture was stirred for 1 hour. Add 8 mL of water, and adjust the pH to 9 _{with solid Na 2} CO _3. The resulting solution was extracted with 2 × 30 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a _{reversed-phase column eluted with water/CH 3} CN (37/63) to obtain 5-(((S)-1-(((R)-2-oxo group) as a white solid -1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)-3-((2,2,2- Trifluoroethyl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one (20 mg, 39% yield). LCMS (ESI, m/z): 647.20 [M+H] ⁺ ; ¹ H NMR(300 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.69 (s, 2H), 7.96 (s, 1H), 6.60 – 6.60 (m, 1H), 4.82 (d, J = 13.2 Hz, 2H), 4.20 – 4.01 (m, 4H), 3.95 – 3.82 (m, 1H), 3.72 – 3.58 (m, 1H), 3.18 – 2.96 (m, 4H), 2.92 – 2.89 (m, 1H), 2.85 – 2.78 (m, 1H), 2.30 – 2.15 (m, 1H), 1.81 – 1.50 (m, 6H).

Example 63 : 5-(((S)-1 -hydroxy- 3-(((R)-2 -oxo- 1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexa hydrogen pyridin-4-yl) pyrrolidin-3-yl) oxy) propan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2 H) - synthesis of ketone.

Step A to (R)-3-((S)-2-amino-3-hydroxypropoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine -4-yl)pyrrolidin-2-one hydrochloride (130 mg, 0.29 mmol, 1.0 equiv) in CH ₃ CN (5 mL), add 5-chloro-2-(4-methoxybenzyl) Glycine)-4-(trifluoromethyl )- 3(2 H )-one (106 mg, 0.33 mmol, 1.1 equiv) and triethylamine (101 mg, 1.00 mmol, 3.4 equiv). The resulting solution was stirred at 60°C for 1.5 days and then concentrated in vacuo. The crude product was applied to a _{reversed-phase column eluted with water/CH 3} CN (1/1) to obtain 150 mg (62% yield) of 5-(((S)-1-hydroxy- 3-(((R)-2-side oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy (Yl)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)pado-3( 2H )-one. LCMS (ES, m/z): 686.20 [M+H] ⁺ .

Step B combines 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa (Hydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)- A solution of 3(2 H )-ketone (150 mg, 0.22 mmol, 1.0 equiv) in TFA/TfOH (1.5 mL, 10:1) was stirred at room temperature for 1 hour, and then by adding ice water (10 mL )Quenched. The pH was neutralized with saturated aqueous NaHCO ₃ solution, and the resulting solution was extracted with 3×30 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography eluted with water/CH ₃ CN (3/2) to obtain 15 mg (12% yield) of 5-(((S)-1-hydroxy-3) as an off-white solid -(((R)-2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy )Propan-2-yl)amino)-4-(trifluoromethyl)pado-3( 2H )-one. LCMS (ESI, m/z): 566.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.45 (br, 1H), 8.69 (s, 1H), 7.95 (s, 1H) , 6.29 – 6.31 (m, 1H), 5.10 (t, J = 5.2 Hz, 1H), 4.82 (d, J = 12.8 Hz, 1H), 4.13 – 4.07 (m, 3H), 3.88 (dd, J = 10.1 , 6.4 Hz, 1H), 3.68 (dd, J = 10.2, 5.4 Hz, 1H), 3.54 (t, J = 5.4 Hz, 2H), 3.28 – 3.22 (m, 1H), 3.16 – 3.10 (m, 1H) , 3.04 (t, J = 11.6 Hz, 2H), 2.29 – 2.21 (m, 1H), 1.77 – 1.50 (m, 5H).

Example 64 : Syn- 5-(((2S)-1-(((3S)-1-(3- hydroxy- 1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridine -4 - yl) -2-oxo pyrrolidin-3-yl) oxy) propan-2-yl) oxy) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one and syn- 5 -(((2S)-1-(((3 R )-1-(3- hydroxy- 1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridin- 4 -yl )-2 --oxo pyrrolidin-3-yl) oxy) propan-2-yl) oxy) (trifluoromethyl) despair 𠯤 -3 (2H) -4- - synthesis of one.

Step A Racemic syn- (3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)aminocarboxylate (2.22 g, 6.13 mmol, 1.0 equiv) in dioxane (10 mL), add 4N HCl (10 mL, 4M) in dioxane. The solution was stirred at 50°C for 1.5 hours and then concentrated in vacuo to obtain 2.28 g (99% yield) of syn -4-amino-1-(5-(trifluoromethyl)pyrimidine- as an off-white solid) 2-yl)hexahydropyridine-3-ol hydrochloride. LCMS (ESI, m/z): 263.05 [M+H] ⁺ .

Step B to syn- 4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-3-ol hydrochloride (2.28 g, 7.63 mmol, 1.0 equiv) in CH ₃ Add imidazole (3.15 g, 46.3 mmol, 6.1 equiv) and tert-butylchlorodimethylsilane (5.80 g, 38.5 mmol, 5.0 equiv) to the solution in CN (20 mL). The mixture was stirred at 60°C for 15 hours and then concentrated in vacuo. The crude product was applied to a silica gel column eluted with DCM/methanol (24/1) to obtain 2.27 g (78% yield) of syn -3-((tertiary butyldimethyl) as a pale yellow solid Silyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine. LCMS (ESI, m/z): 377.10 [M+H] ⁺ .

Step C to syn-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine (2.27 g , 6.03 mmol, 1.0 equiv) in DCM (50 mL) was added (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane-4- Base) acetaldehyde (5.70 g, 36.0 mmol, 5.98 equiv) and AcOH (1.08 g, 17.9 mmol, 3.0 equiv). The resulting solution was stirred for 1 hour, and then STAB (3.84 g, 18.1 mmol, 3.0 equiv) was added, and the mixture was stirred for another 3 hours. After completion, the reaction was quenched by adding 50 mL saturated aqueous sodium bicarbonate solution and extracted with 3×60 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with DCM/methanol (24/1) to obtain 2.55 g (81% yield) of syn -(3S)-1-(3-((第Tributyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one. LCMS (ESI, m/z): 461.15 [M+H] ⁺ .

Step D to syn-(3S)-1-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine -4-yl)-3-hydroxypyrrolidin-2-one (2.40 g, 5.21 mmol, 1.0 equiv) in DCM (30 mL) was added triethylamine (2.19 g, 21.6 mmol, 4.2 equiv), 4-Toluenesulfonyl chloride (2.04 g, 10.7 mmol, 2.1 equiv) and DMAP (0.13 g, 1.07 mmol, 0.2 equiv). The resulting solution was stirred at room temperature overnight, and then the reaction was quenched by adding 50 mL of ice water. The solution was extracted with 2×100 mL DCM, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (1:2 to 10:1) to obtain 3.4 g (99% yield) of syn-(3S)- as a pale yellow solid 4-Toluenesulfonic acid 1-(3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl )-2-oxopyrrolidin-3-yl ester. LCMS (ESI, m/z): 615.20 [M+H] ⁺ .

Step E Add (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (1.09 g, 6.80 mmol, 2.0 equiv) in DMF (20 mL Add NaH (0.27 g, 6.85 mmol, 2.0 equiv, 60% dispersion in mineral oil) to the solution in ). The reaction mixture was stirred for 15 min, and then syn-(3S)-4-toluenesulfonic acid 1-(3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoro (Methyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl ester (2.10 g, 3.42 mmol, 1.0 equiv), and the solution was stirred at room temperature for 1 Hour. The reaction was treated with MeOH (5 mL), concentrated in vacuo and applied to a silica gel column eluted with ethyl acetate/petroleum ether (1/2) to obtain 775 mg (38% yield) of an off-white solid Syn-1-(3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)- 3-((2S)-2-((Tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyrrolidin-2-one. LCMS (ESI, m/z): 603.20 [M+H] ⁺ .

Step F to syn-1-(3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl )-3-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyrrolidin-2-one (500 mg, 0.8 mmol, 1 equiv) in MeOH Add pyridinium p-toluenesulfonate (210 mg, 0.83 mmol, 1.0 equiv) to the solution in (30 mL). The resulting solution was stirred at room temperature for 15 hours and then quenched by the addition of solid Na ₂ CO ₃ (200 mg). The resulting mixture was concentrated and applied to a silica gel column eluted with ethyl acetate to obtain 350 mg (79% yield) of 1-syn-3-((tertiary butyldimethylsilyl) as a light yellow solid )Oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-((S)-2-hydroxypropoxy)pyrrolidine-2- ketone. LCMS (ESI, m/z): 519.20 [M+H] ⁺ .

Step G Add syn-1-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-3-((S)-2-hydroxypropoxy)pyrrolidin-2-one (360 mg, 0.70 mmol, 1.0 equiv) in DCM (5 mL), add 5-chloro- 2-[(4-Methoxyphenyl)methyl]-4-(trifluoromethyl)pak-3-one (301 mg, 0.95 mmol, 1.4 equiv) and t-BuOK (290 mg, 2.6 mmol , 3.8 equiv). The resulting solution was stirred for 1.5 hours and then concentrated and applied to a silica gel column eluted with ethyl acetate/petroleum ether (1/1) to obtain 471 mg (85% yield) of white solid syn-5- (((2S)-1-((1-3-((tert-butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine -4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)oxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl ) Da 𠯤-3(2H)-ketone. LCMS (ESI, m/z): 801.3 [M+H] ⁺ .

Step H will syn-5-(((2S)-1-((1-3-((tertiary butyldimethylsilyl)oxy)-1-(5-(trifluoromethyl)pyrimidine- 2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)oxy)-2-(4-methoxybenzyl)- A solution of 4-(trifluoromethyl) 𠯤-3(2H)-one (471 mg, 0.59 mmol, 1.0 equiv) in TFA/TfOH (3 mL, 10:1) was stirred at room temperature for 2 hours. By adding ice water (20 mL) quenched the reaction and the pH was adjusted to 7 with a saturated aqueous solution of Na ₂ CO _3. The solution was extracted with 3×60 mL ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to _{reversed-phase chromatography eluted with water/CH 3} CN (1/1) and further purified by chiral prep HPLC with the following conditions: CHIRAL ART Cellulose-SB, 2*25 cm, 5 µm; Mobile phase A: Hex:DCM = 3:1 (10 mM NH ₃ -MeOH); mobile phase B: IPA; flow rate: 20 mL/min; gradient: 30% B for 7 min; 220/254 nm. The absolute stereochemistry of the pyrrolidone stereocenter is assigned by similar to Example 10, based on the efficacy of PARP7 of the more active diastereomer, and similar to the X-ray crystal structure of Example 10B. The absolute stereochemistry of the stereocenter of hexahydropyridine has not been determined.

Example 64 Isomer A (64A) : Syn-5-(((2S)-1-(((3S)-1-(3-hydroxy-1-(5-(trifluoromethyl)pyrimidine-2- Yl)hexahydropyridin-4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)phat-3(2H )-Ketone (61 mg, 25% yield, off-white solid). LCMS (ESI, m/z): 567.20[M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.22 (s, 1H), 8.65 (s, 2H), 8.28 (s, 1H), 5.22 – 5.15 (m, 1H), 5.00 (br, 1H), 4.90 – 4.72 (m, 2H), 4.06 – 3.95 (m, 3H) , 3.90 (s, 1H), 3.63 (dd, J = 11.1, 8.0 Hz, 1H), 3.30 – 3.24 (m, 2H), 3.14 – 2.98 (m, 2H), 2.20 – 2.16 (m, 1H), 2.07 – 2.02 (m, 1H), 1.61 – 1.58 (m, 1H), 1.49 – 1.41 (m, 1H), 1.28 (d, J = 6.2 Hz, 3H). Chiral HPLC: CHIRAL Cellulose-SB, 0.46*10 cm; 3 µm; (Hex:DCM = 3:1 w/ 0.1% diethylamine: IPA = 90:10; flow rate: 1 mL/min); retention time: 3.726 min. (faster peak).

Example 64 Isomer B (64B) : Syn-5-(((2S)-1-(((3R)-1-(3-hydroxy-1-(5-(trifluoromethyl)pyrimidine-2- Yl)hexahydropyridin-4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)phat-3(2H )-Ketone (144 mg, 59% yield, off-white solid). LCMS (ESI, m/z): 567.10[M+H] ^{+ 1} H NMR (400 MHz, DMSO- d ₆ ) δ 13.21 (s, 1H ), 8.65 (s, 2H), 8.31 (s, 1H), 5.19 – 5.15 (m, 1H), 5.00 (br, 1H), 4.88 – 4.76 (m, 2H), 4.07 (t, J = 7.4 Hz, 1H), 4.04 – 3.98 (m, 1H), 3.93 – 3.83 (m, 2H), 3.74 (dd, J = 11.1, 3.3 Hz, 1H), 3.30 – 3.24 (m, 2H), 3.17 – 2.98 (m, 2H), 2.28 – 2.17 (m, 1H), 2.11 – 1.97 (m, 1H), 1.71 – 1.62 (m, 1H), 1.47 (d, J = 12.2 Hz, 1H), 1.28 (d, J = 6.2 Hz , 3H). Chiral HPLC: CHIRAL Cellulose-SB, 0.46*10 cm; 3 µm; (Hex:DCM = 3:1 w/ 0.1% diethylamine: IPA = 90:10; flow rate: 1 mL/min); retention time: 5.703 min. (slower peak).

Example 65 : 5-(((2S)-1-((1-((3R,4R)-3 -hydroxy- 1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridine -4 - yl) -2-oxo pyrrolidin-3-yl) oxy) propan-2-yl) oxy) (trifluoromethyl) despair 𠯤 -3 (2H) -4- - one synthesis of

Step A Adds ((3R,4R)-3-hydroxyhexahydropyridin-4-yl)amino acid tert-butyl ester (2.00 g, 9.25 mmol, 1.00 equiv), 2-chloro-5-(trifluoromethyl ) Pyrimidine (1.69 g, 9.25 mmol, 1.00 equiv) in DMF (20 mL) was added with K ₂ CO ₃ (2.56 g, 18.5 mmol, 2.00 equiv). The resulting solution was stirred at 50°C for 2 hours and quenched by adding 50 mL of ice water. The solid was collected by filtration to obtain 2.8 g (84% yield) of ((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro as a white solid (Pyridin-4-yl)carbamic acid tert-butyl ester. LCMS (ESI, m/z): 363.10 [M+H] ⁺ .

Step B: ((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)aminocarboxylate (2.80 g, A solution of 7.73 mmol, 1.00 equiv) in 4N HCl (20 mL) in dioxane was stirred for 1 hour. The mixture was concentrated to obtain 2.6 g of crude (3R,4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-3-ol as a clear oil. Continue to use after further purification. LCMS (ESI, m/z): 263.05 [M+H] ⁺ .

Step C : Add (3R, 4R)-4-amino-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-3-ol (2.60 g, 9.92 mmol, 1.00 equiv) in CH Add tertiary butyldimethylsilyl chloride (5.98 g, 39.7 mmol, 4.00 equiv) and imidazole (5.40 g, 79.3 mmol, 8.00 equiv) to the solution in _{3 CN (15 mL).} The resulting solution was stirred at 60°C for 4 hours and then concentrated in vacuo and applied to a silica gel column eluted with DCM/methanol (99/1) to obtain 2.5 g (67% yield) of yellow oil (3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine. LCMS (ESI, m/z): 377.15 [M+H] ⁺ .

Step D adds (3R, 4R)-3-(tertiary butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4-amine ( 3.20 g, 8.50 mmol, 1.0 equiv) in DCM and DMF (1:1, 90 mL), add (S)-2-(2,2-dimethyl-5-oxo-1,3 -Dioxolane-4-yl)acetaldehyde (2.69 g, 17.0 mmol, 2.0 equiv), STAB (7.21 g, 34.0 mmol, 4.0 equiv) and AcOH (0.51 g, 8.5 mmol, 1.0 equiv). The solution was stirred for 6 hours and then quenched by adding 90 mL of water. The solution was extracted with 3×180 mL DCM, and the combined organics were concentrated in vacuo. The crude residue was applied to a silica gel column with DCM/methanol (95/5) to obtain 1.9 g (49% yield) of (S)-1-((3R,4R)-3- (Tertiary butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-3-hydroxypyrrolidin-2-one. LCMS (ESI, m/z): 461.20 [M+H] ⁺ .

Step E to (S)-1-((3R,4R)-3-(tertiary butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa Add hydropyridin-4-yl)-3-hydroxypyrrolidin-2-one (1.00 g, 2.17 mmol, 1.0 equiv) and TsCl (496 mg, 2.61 mmol, 1.2 equiv) in DCM (10 mL) DMAP (265 mg, 2.17 mmol, 1.0 equiv) and triethylamine (439 mg, 4.34 mmol, 2.0 equiv). The solution was stirred for 2 hours and then saturated aqueous NaHCO ₃ solution was added. The layers were separated and the aqueous layer was extracted with 3×10 mL DCM. The combined organic layer was washed with 3×30 mL saturated aqueous NaHCO ₃ solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was applied to a silica gel column eluted with ethyl acetate/petroleum ether (1/1) to obtain 1.0 g (75% yield) of (S)-4-toluenesulfonic acid 1- ((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2 -Pendant oxypyrrolidin-3-yl ester. LCMS (ESI, m/z): 615.30 [M+H] ⁺ .

Step F Add (S)-4-toluenesulfonic acid 1-((3R,4R)-3-(tertiary butyldimethylsilyloxy)-1-(5-(trifluoromethyl) at 0℃ (Pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl ester (540 mg, 0.88 mmol, 1.0 equiv) in DMF (5 mL) NaH (42 mg, 1.8 mmol, 2.0 equiv, 60% dispersion in mineral oil), and the mixture was stirred at 0°C for 15 min. (2S)-2-(oxiran-2-yloxy)propan-1-ol (281 mg, 1.76 mmol, 2.0 equiv) was added, and the mixture was stirred for another 30 min. Then the reaction was quenched by adding 10 mL MeOH, concentrated in vacuo, and applied to a silica gel column eluted with ethyl acetate/petroleum ether (1/1) to obtain 181 mg (34% yield) White solid 1-((3R,4R)-3-(tertiary butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4 -Yl)-3-((S)-2-(tetrahydro-2H-pyran-2-yloxy)propoxy)pyrrolidin-2-one. LCMS (ESI, m/z): 519.25 [M+H] ⁺ .

Step G to 1-((3R,4R)-3-(tertiary butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4 -Yl)-3-((S)-2-(tetrahydro-2H-pyran-2-yloxy)propoxy)pyrrolidin-2-one (180 mg, 0.30 mmol, 1.0 equiv) in MeOH Add pyridinium p-toluenesulfonate (75 mg, 0.30 mmol, 1.0 equiv) to the solution in (5 mL). The resulting solution was stirred at 40°C for 1 hour and then concentrated and applied to a silica gel column eluted with ethyl acetate/petroleum ether (4/1) to obtain 127 mg (82% yield) of a white solid 1 -((3R,4R)-3-(tert-butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)- 3-((S)-2-hydroxypropoxy)pyrrolidin-2-one. LCMS (ESI, m/z): 519.20 [M+H] ⁺ .

Step H at 0 ℃ to 1-((3R,4R)-3-(tertiary butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa Hydropyridin-4-yl)-3-((S)-2-hydroxypropoxy)pyrrolidin-2-one (120 mg, 0.2 mmol, 1 equiv) in DCM (5 mL), add t -BuOK (50 mg, 0.5 mmol, 2 equiv). The resulting solution was stirred for 15 min, and then 5-chloro-2-(4-methoxybenzyl)-4-(trifluoromethyl)- 3(2H)-one (86 mg, 0.27 mmol, 1.2 equiv), and the mixture was stirred at 0°C for 1.5 hours. The mixture was concentrated, and the residue was applied to a silica gel column eluted with ethyl acetate/petroleum ether (4/1) to obtain 62 mg (34% yield) of a white solid 5-((S)- 1-(1-((3R,4R)-3-(tertiary butyldimethylsilyloxy)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4 -Yl)-2-lateral oxypyrrolidin-3-yloxy)prop-2-yloxy)-2-(4-methoxybenzyl)-4-(trifluoromethyl)- 3(2H)-ketone. LCMS (ESI, m/z): 801.35 [M+H] ⁺ .

Step I will 5-[[(2S)-1-([1-[(3R,4R)-3-[(tertiary butyldimethylsilyl)oxy]-1-[5-(trifluoro (Methyl)pyrimidin-2-yl]hexahydropyridin-4-yl]-2-oxopyrrolidin-3-yl]oxy)prop-2-yl]oxy]-2-[(4-methyl A solution of oxyphenyl)methyl)-4-(trifluoromethyl)pado-3-one (60 mg, 0.08 mmol, 1 equiv) in TFA and TfOH (3 mL, 10:1) in 0 Stir for 4 hours at °C and then dilute with 10 mL ice water. The pH was adjusted to 7 by adding saturated aqueous NaHCO _{3 solution.} The resulting solution was extracted with 3×20 mL ethyl acetate, and the combined organic layer was concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluted with water/CH ₃ CN (1/1) to obtain 7 mg (14% yield) of 5-(((2S)-1-((1-( (3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy )Propan-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one. LCMS (ESI, m/z): 567.40 [M+H] ⁺ ; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 13.21 (s, 1H), 8.69 (s, 2H), 8.31-8.27 (m, 1H), 5.31-5.20 (m, 1H), 5.19-5.12 (m, 1H), 4.89-4.81 (m, 1H), 4.73 (d, J = 13.2 Hz, 1H), 4.14-3.69 (m, 4H) , 3.64-3.39 (m, 2H), 3.17-3.09 (m, 2H), 3.05-2.91 (m, 1H), 2.80-2.69 (m, 1H), 2.27-2.18(m, 1H), 1.62-1.50 ( m, 3H), 1.26 (d, J = 6.3 Hz, 3H).

Example 66 : N-((S)-3-(((R)-2 -oxo- 1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridine- 4- yl) pyrrolidin-3-yl) oxy) -2 - ((6-oxo-5- (trifluoromethyl) -1,6-dihydropyridazine 𠯤 4-yl) amino) propyl ) Synthesis of Acetamide .

Step A to 5-(((2S)-1-amino-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl) Hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl) -3(2H)-ketone (70 mg, 0.1 mmol, 1 equiv) in DCM (3 mL) was added DMAP (1 mg, 0.01 mmol, 0.1 equiv), acetic anhydride (15 mg, 0.15 mmol, 1.5 equiv) and triethylamine (31 mg, 0.31 mmol, 3 equiv). The resulting solution was stirred for 1 hour and then diluted with 60 mL of ethyl acetate. The mixture was washed with 3×20 ml water and then dried over anhydrous sodium sulfate and concentrated to obtain N-((S)-2-((1-(4-methoxybenzyl)-6-side Oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)-3-(((R)-2-oxo-1-(1-(5 -(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propyl)acetamide (66 mg, 71% yield). LCMS (ESI, m/z): 727.25 [M+H] ⁺ .

Step B to N-((S)-2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydro 4-yl)amino)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl) To a solution of pyrrolidin-3-yl)oxy)propyl)acetamide (66 mg, 0.090 mmol, 1.0 equiv) in TFA (1 mL) was added TfOH (0.1 mL), and the mixture was stirred for 1 hour. The reaction was quenched by adding 8 mL of water, and the pH was adjusted to 9 _{with saturated aqueous Na 2} CO _3. The resulting solution was extracted with 2 × 30 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a _{C18 reversed-phase column eluted with water/CH 3} CN (47/53) to obtain N-((S)-3-(((R)-2-oxo group) as a white solid -1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)-2-((6-side oxy- 5-(Trifluoromethyl)-1,6-dihydrotap-4-yl)amino)propyl)acetamide (13 mg, 22% yield). LCMS (ESI, m/z): 607.30 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 12.49 (s, 1H), 8.69 (s, 2H), 8.14 (t, J = 5.9 Hz, 1H), 7.98 (s, 1H), 6.55 – 6.44 ( m, 1H), 4.82 (d, J = 13.2 Hz, 2H), 4.21 – 4.02 (m, 3H), 3.90 – 3.81 (m, 1H), 3.70 – 3.61 (m, 1H), 3.30 – 2.96 (m, 6H), 2.31 – 2.15 (m, 1H), 1.81 (s, 3H), 1.81 – 1.45 (m, 5H).

Example 67 : 5-(((2R,3R)-3 -hydroxy- 1-(((R)-2 -oxo- 1-(1-(5-( trifluoromethyl ) pyrimidin -2- yl) ) hexahydro-4-yl) pyrrolidin-3-yl) oxy) butan-2-yl) amino) -4- (trifluoromethyl) despair 𠯤 -3 (2H) - one synthesis of

Step A : Add (4R,5R)-4-(hydroxymethyl)-2,2,5-trimethyloxazolidine-3-acetic acid tert-butyl ester (4.0 g, 16 mmol, 1.0 equiv) in DCM ( Add 4-toluenesulfonyl chloride (3.7 g, 20 mmol, 1.2 equiv), DMAP (1.9 g, 16 mmol, 1.0 equiv) and triethylamine (3.3 g, 32.6 mmol, 2.0 equiv) to the solution in 10 mL) . The resulting solution was stirred for 4 hours and then washed with 2×25 mL saturated aqueous NaHCO ₃ solution. The organic layer was concentrated and applied to a silica gel column eluted with ethyl acetate/petroleum ether (9/1) to obtain 5.8 g (89% yield) of yellow oil (4R,5R)-2,2, 5-trimethyl-4-((tosyloxy)methyl)oxazolidine-3-acetic acid tert-butyl ester. LCMS (ESI, m/z): 344.05 [M+H] ⁺ .

Step B: Add (R)-3-hydroxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one ( 500 mg, 1.51 mmol, 1.0 equiv) NaH (72 mg, 3.0 mmol, 2.0 equiv, 60% dispersion in oil) was added to a solution in DMF (5 mL). The mixture was stirred for 10 minutes and then (4R,5R)-2,2,5-trimethyl-4-((tosyloxy)methyl)oxazolidine-3-acetic acid was added at 0°C. Tributyl ester (1.8 g, 4.5 mmol, 3.0 equiv). The reaction mixture was stirred for another 6 hours at 40°C and then concentrated and purified by silica gel chromatography eluted with ethyl acetate/petroleum ether (15/85) to obtain 900 mg of yellow oil (4R, 5R)- 2,2,5-Trimethyl-4-((((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4 -Yl)pyrrolidin-3-yl)oxy)methyl)oxazolidine-3-acetic acid tert-butyl ester. LCMS (ESI, m/z): 558.25 [M+H] ⁺ .

Step C will (4R,5R)-2,2,5-trimethyl-4-((((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine- 2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)methyl)oxazolidine-3-acetic acid tert-butyl ester (900 mg, 1.6 mmol, 1.0 equiv) in dioxane The solution in 4M HCl (10 mL) was stirred for 6 hours and then concentrated to obtain 850 mg of colorless oil (R)-3-((2R,3R)-2-amino-3-hydroxybutoxy )-1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-2-one hydrogen chloride, which was used without further purification. LCMS (ESI, m/z): 418.10 [M+H] ⁺ .

Step D to (R)-3-((2R,3R)-2-amino-3-hydroxybutoxy)-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa Hydropyridin-4-yl)pyrrolidin-2-one hydrogen chloride (400 mg, 0.96 mmol, 1.0 equiv) in isopropanol (5 mL) was added with 5-chloro-2-(4-methoxybenzyl) Yl)-4-(trifluoromethyl)pado-3(2H)-one (366 mg, 1.15 mmol, 1.2 equiv) and N,N-diisopropylethylamine (620 mg, 4.8 mmol, 5.0 equiv ). The solution was stirred at 80°C for 6 hours and then concentrated and applied to a silica gel column eluted with ethyl acetate/petroleum ether (95/5) to obtain 170 mg (25% yield) of a yellow solid 5 -(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine -4-yl)pyrrolidin-3-yl)oxy)but-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl)da 𠯤-3( 2H)-ketone. LCMS (ESI, m/z): 700.20 [M+H] ⁺ .

Step E The 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl )Hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)but-2-yl)amino)-2-(4-methoxybenzyl)-4-(trifluoromethyl) A solution of 𠯤-3(2H)-ketone (120 mg, 0.17 mmol, 1.0 equiv) in TFA/TfOH (3 mL, 3:1) was stirred at -10°C for 40 min. The pH was adjusted to ~6-7 with saturated _{aqueous Na 2} CO ₃ and the resulting solution was extracted with 3×25 mL ethyl acetate. The organic layers were combined, _{dried over Na 2} SO ₄ and concentrated. The crude product was purified by C18 reverse phase chromatography with CH ₃ CN/water to obtain 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo) as a white solid Base-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)but-2-yl)amino)- 4-(Trifluoromethyl)taka-3(2H)-one 55 mg (55% yield). LCMS (ESI, m/z): 580.20 [M+H] ⁺ ; ¹ H-NMR (300 MHz, DMSO- d ₆ ) δ 12.45 (s, 1H), 8.67 (s, 2H), 7.93 (s, 1H ), 6.25-6.12 (m, 1H), 5.29 (d, J = 4.1 Hz, 1H), 4.80 (d, J = 13.2 Hz, 2H), 4.15-4.07 (m, 2H), 3.96-3.82 (m, 3H), 3.69-3.61 (m, 1H), 3.28-2.94 (m, 4H), 2.25-2.16 (m, 1H), 1.79-1.53 (m, 5H), 1.07 (d, J = 6.2 Hz, 3H) .

Example 68 : 4-((R)-2 - Pendant oxy -3-((S)-2-((6 -Pendent oxy -5-( trifluoromethyl )-1,6-dihydrogen) -4 -yl ) amino ) propoxy ) pyrrolidin- 1 -yl )-1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridine- 3 -carboxamide

Step A to 4-aminohexahydropyridine-1,3-dicarboxylate 1-(tert-butyl) 3-ethyl ester (16.0 g, 58.7 mmol, 1.00 equiv) in DCM (200 mL) Add AcOH (5.29 g, 88.1 mmol, 1.50 equiv) and (R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolane-4-yl)acetaldehyde (10.2 g, 64.6 mmol, 1.1 equiv). The resulting solution was stirred at room temperature for 5 hours, and then STAB (24.9 g, 117 mmol, 2.0 equiv) was added, and the reaction mixture was stirred for another 45 hours. The solution was quenched by adding 100 mL of ice water, and the pH was adjusted to 8 with 1% NaOH aqueous solution. The solution was extracted with 300 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was applied to a silica gel column eluted with ethyl acetate/petroleum ether (1/9) to obtain 5.7 g (27% yield) of brown oily 4-((R)-3-hydroxy- 2-Pyrridine-1-yl)hexahydropyridine-1,3-dicarboxylate 1-(tert-butyl) 3-ethyl ester.

In step B, 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-1,3-dicarboxylate 1-(tert-butyl) 3-ethyl ester A solution of (5.70 g, 16.0 mmol, 1.0 equiv) in 4N HCl (40 mL) in dioxane was stirred for 20 hours. The resulting mixture was concentrated in vacuo to obtain 5 g of 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-3-ethyl acetate hydrochloride as a brown solid, It was used without further purification.

Step C Add 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)hexahydropyridine-3-ethyl acetate hydrochloride (5.00 g, 17.1 mmol, 1.0 equiv) in DMF Add 2-chloro-5-(trifluoromethyl)pyrimidine (3.12 g, 17.1 mmol, 1.0 equiv) and K ₂ CO ₃ (7.08 g, 51.2 mmol, 3.0 equiv) to the solution in (40 mL). The resulting solution was stirred at 60°C for 1 hour and concentrated in vacuo and _{purified by reverse phase chromatography eluted with water/CH 3} CN (9/11) to obtain 1.2 g (17% yield) of a yellow solid 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-acetic acid ethyl ester ester. LCMS (ESI, m/z): 403.2 [M+H] ⁺ .

Step D adds 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3- Add NaOH (111 mg, 2.78 mmol, 2.0 equiv) to a solution of ethyl acetate (558 mg, 1.39 mmol, 1.0 equiv) in EtOH (5 mL) and water (1 mL). The resulting solution was stirred for 15 hours. The pH was adjusted to 5 with HCl (2 M) and concentrated in vacuo. The residue was applied to a _{silica gel column eluted with water/CH 3} CN (5:1) to obtain 420 mg (81% yield) of 4-((R)-3-hydroxy-2- Pendant oxypyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carboxylic acid. LCMS (ESI, m/z): 375.10 [M+H] ⁺ .

Step E to 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3- To a solution of formic acid (420 mg, 1.1 mmol, 1.0 equiv) in DMF (5 mL), add N,N-diisopropylethylamine (290 mg, 2.2 mmol, 2.0 equiv), NH ₄ Cl (90 mg, 1.7 mmol, 1.5 equiv) and HATU (640 mg, 1.7 mmol, 1.5 equiv). The resulting solution was stirred for 1.5 hours and then applied to a _{reversed-phase C18 column eluted with water/CH 3} CN (5:1) to obtain 400 mg (95% yield) of 4-((R) as a yellow solid -3-Hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carboxamide. LCMS (ESI, m/z): 374.10 [M+H] ⁺ .

Step F at 0℃ to 4-((R)-3-hydroxy-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro Add NaH (86 mg, 2.2 mmol, 2.0 equiv, 60% dispersion in oil) to a solution of pyridine-3-carboxamide (400 mg, 1.1 mmol, 1.0 equiv) in DMF (20 mL). After 15 minutes, add (4S)-4-methyl-2,2-dioxo-1,2λ6,3-oxathiazolidine-3-acetic acid tert-butyl ester (265 mg, 1.12 mmol, 1.0 equiv ) In DMF (2 mL), and the mixture was stirred for 1 hour. The reaction was quenched by adding 2 mL of saturated aqueous sodium bicarbonate solution. The resulting mixture was concentrated and applied to a _{reversed-phase column eluted with water/CH 3} OH (11:9) to obtain 330 mg (48% yield) of ((2S)-1-(((3R) )-1-(3-aminomethanyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl) (Oxy)prop-2-yl)carbamic acid tert-butyl ester. LCMS (ESI, m/z): 531.30 [M+H] ⁺ .

Step G: ((2S)-1-(((3R)-1-(3-aminomethanyl-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl) )-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)aminocarboxylate (330 mg, 0.62 mmol, 1.0 equiv) in dioxane in 4N HCl (5 mL) was stirred for 1 hour, and then concentrated in vacuo to obtain 305 mg (66% yield) of 4-((R)-3-((S)-2-aminopropyl) as a pale yellow solid (Oxy)-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carboxamide hydrochloride. LCMS (ESI, m/z): 431.20 [M+H] ⁺ .

Step H to 4-((R)-3-((S)-2-aminopropoxy)-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl) Pyrimidine-2-yl)hexahydropyridine-3-carboxamide hydrochloride (280 mg, 0.60 mmol, 1.0 equiv) in CH ₃ CN (5 mL), add N,N-diisopropyl ethyl Amine (280 mg, 2.2 mmol, 3.6 equiv) and 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)3-ketone (201 mg, 0.63 mmol, 1.1 equiv). The solution was stirred at 80°C for 1 hour and then concentrated in vacuo. The crude product was applied to a _{reversed-phase C18 column eluted with water/CH 3} CN (1/1) to obtain 290 mg (63% yield) of 4-((R)-3-(( S)-2-((1-(4-Methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)amino) Propoxy)-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carboxamide. LCMS (ESI, m/z): 713.25 [M+H] ⁺ .

Step 1 The 4-((R)-3-((S)-2-((1-(4-methoxybenzyl)-6-pendant oxy-5-(trifluoromethyl)-1, 6-Dihydrota(4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa A solution of hydropyridine-3-carboxamide (570 mg, 0.80 mmol, 1.0 equiv) in TFA/TfOH (5 mL, 10:1) was stirred for 1 hour. By the addition of 15 mL The reaction was quenched with ice water, and the pH was adjusted to ~ 7-8 with ₂ CO ₃ saturated aqueous Na. The solution was extracted with 3 x 60 mL DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography eluted with water/CH ₃ CN (3/2) to obtain 314 mg (66% yield) of 4-((R)-2-oxo- 3-((S)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotap-4-yl)amino)propoxy)pyrrolidine-1 -Yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carboxamide. LCMS (ESI, m/z): 593.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.46 (s, 1H), 8.74 (s, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.53-7.48 (m, 1H), 6.99 (s, 1H), 6.37-6.29 (m, 1H), 4.89-4.76 (m, 2H), 4.33 – 4.01 (m, 3H), 3.86 -3.73 (m, 1H), 3.63-3.53 (m, 1H), 3.29-3.20 (m, 1H), 3.15-3.00 (m, 3H), 2.68 – 2.53 (m, 1H), 2.31-2.12 (m, 1H), 1.82 – 1.56 (m, 3H), 1.19-1.13 (m, 3H).

向4-((R)-2-側氧基-3-((S)-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)吡咯啶-1-基)-1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-3-甲醯胺(320 mg, 0.54 mmol, 1.0 equiv)於水(22 mL)及CH₃ CN (27 mL)中之溶液中添加氯化鈀(133 mg, 0.75 mmol, 1.4 equiv)。將所得溶液於80℃下攪拌過夜且然後用4 × 30 mL乙酸乙酯萃取。合併有機層，經無水硫酸鈉乾燥且濃縮。將殘餘物施加至用水/CH₃ CN (1/1)溶析之C18反相管柱上，從而得到15 mg (5%產率)之白色固體狀4-((R)-2-側氧基-3-((S)-2-((6-側氧基-5-(三氟甲基)-1,6-二氫嗒𠯤-4-基)胺基)丙氧基)吡咯啶-1-基)-1-(5-(三氟甲基)嘧啶-2-基)六氫吡啶-3-甲腈。LCMS (ESI, m/z): 575.25 [M+H]⁺ ；¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.46 (s, 1H), 8.85 (s, 2H), 7.95 (d,J = 3.6 Hz, 1H), 6.32 (br, 1H), 5.13 – 5.01 (m, 1H), 4.93 – 4.76 (m, 1H), 4.46 – 4.34 (m, 1H), 4.28 – 4.12 (m, 2H), 3.86 – 3.75 (m, 1H), 3.68 – 3.58 (m, 1H), 3.49 – 3.39 (m, 1H), 3.26 – 3.08 (m, 3H), 2.32 – 2.24 (m, 1H), 1.99 – 1.58 (m, 3H), 1.28 – 1.13 (m, 4H)。 Example 69 : 4-((R)-2 - Pendant oxy -3-((S)-2-((6 -Pendent oxy -5-( trifluoromethyl )-1,6-dihydro) -4 -yl ) amino ) propoxy ) pyrrolidin- 1 -yl )-1-(5-( trifluoromethyl ) pyrimidin -2- yl ) hexahydropyridine- 3 -carbonitrile .

To 4-((R)-2-side oxy-3-((S)-2-((6-side oxy-5-(trifluoromethyl)-1,6-dihydro 𠯤-4 -Yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carboxamide (320 mg, 0.54 mmol , 1.0 equiv) Add palladium chloride (133 mg, 0.75 mmol, 1.4 equiv) to a solution of water (22 mL) and CH _{3 CN (27 mL).} The resulting solution was stirred at 80°C overnight and then extracted with 4×30 mL ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied to a _{C18 reversed-phase column eluted with water/CH 3} CN (1/1) to obtain 15 mg (5% yield) of 4-((R)-2-oxo -3-((S)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy)pyrrolidine -1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carbonitrile. LCMS (ESI, m/z): 575.25 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.46 (s, 1H), 8.85 (s, 2H), 7.95 (d, J = 3.6 Hz, 1H), 6.32 (br, 1H), 5.13 – 5.01 (m, 1H), 4.93 – 4.76 (m, 1H), 4.46 – 4.34 (m, 1H), 4.28 – 4.12 (m, 2H), 3.86 – 3.75 (m, 1H), 3.68 – 3.58 (m, 1H), 3.49 – 3.39 (m, 1H), 3.26 – 3.08 (m, 3H), 2.32 – 2.24 (m, 1H), 1.99 – 1.58 (m, 3H), 1.28 – 1.13 (m, 4H).

其中TRF_cmpd 係來自化合物處理之孔之TR-FRET比率，TRF_min 係來自5-(5-(六氫吡啶-4-基氧基)異吲哚啉-2-基)-4-(三氟甲基)嗒𠯤-3(2H)-酮處理之陽性對照孔之TR-FRET比率且TRF_max 係來自DMSO處理之陰性對照孔之TR-FRET比率。 繪製抑制%值隨化合物濃度變化之圖且應用以下4-參數擬合以衍生IC₅₀ 值：

其中通常允許頂部值及底部值浮動，但在3-參數擬合中可分別固定為100或0。通常允許希爾係數浮動，但在3-參數擬合中亦可固定為1。Y係抑制%且X係化合物濃度。 Example A. Enzyme analysis of inhibition of PARP7 The displacement of probe A (biotinylated probe bound to the active site of TIPARP) was measured using time-resolved fluorescent energy transfer (TR-FRET) analysis. Use Mosquito (TTP Labtech) to spot the dose-response curve of each of 20 nL and the test compound on black 384-well polyphenylene acetylene proxiplates (Perkin Elmer). By adding 6 μL TIPARP and probe A in assay buffer (20 mM HEPES pH = 8, 100 mM NaCl, 0.1% bovine serum albumin, 2 mM DTT and 0.002% Tween20), and test compound at 25°C Incubate together for 30 min, and then add 2 μL ULight-anti 6xHis and LANCE Eu-W1024 labeled Streptavidin (Perkin Elmer) to perform the reaction in a volume of 8 μL. The final concentrations of TIPARP and Probe A are 6 nM and 2 nM, respectively. The final concentrations of ULight-anti 6xHis and LANCE Eu-W1024 labeled streptavidin are 4 nM and 0.25 nM, respectively. The reaction was incubated for another 30 min at 25°C, and then used on an Envision plate reader equipped with a LANCE/DELFIA top mirror (Perkin Elmer) with 320 nM excitation and 615 nM and 665 nM emission readings with a delay of 90 μs. Calculate the 665/615 nm emission ratio of each well to determine the amount of TIPARP and probe A complex in each well. Use a negative control containing 0.25% DMSO vehicle or 100 μM 5-(5-(hexahydropyridin-4-yloxy)isoindolin-2-yl)-4-(trifluoromethyl) 𠯤- For control wells of 3(2H)-ketone positive control, calculate the% inhibition as follows:

Wherein TRF _cmpd is derived from the TR-FRET ratio of compound-treated holes, and TRF _min is derived from 5-(5-(hexahydropyridin-4-yloxy)isoindolin-2-yl)-4-(trifluoro The TR-FRET ratio of the positive control wells treated with meth)pada-3(2H)-ketone and TRF _max is the TR-FRET ratio from the negative control wells treated with DMSO. % Inhibition plotted with values showing variation of concentration of compound and in the following 4-parameter fit to derive IC ₅₀ values:

The top value and bottom value are usually allowed to float, but can be fixed to 100 or 0 respectively in 3-parameter fitting. The Hill coefficient is usually allowed to float, but it can also be fixed to 1 in 3-parameter fitting. Y series inhibition% and X series compound concentration.

Synthesis of Probe A

Step A: Add 5-chloro-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydro at 60°C 3-ketone (2.8 g, 8.52 mmol, 1.00 equiv), 2,3-dihydro-1H-isoindole-5-ol hydrobromide (4.27 g, 19.76 mmol, 1.00 equiv) and TEA (10 mL) The solution in ethanol (40 mL) was stirred for 1 h. The resulting solution was extracted with 2 × 100 mL ethyl acetate and the organic layers were combined and concentrated under reduced pressure to obtain 4.5 g of yellow oily 5-(5-hydroxy-2,3-dihydro-1H-isoindole-2 -Yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydrota 𠯤-3-one. LCMS: [M+H] ⁺ 428.23.

In step B, 5-(5-hydroxy-2,3-dihydro-1H-isoindol-2-yl)-4-(trifluoromethyl)-2-[[2-(trimethylsilyl) Ethoxy]methyl)-2,3-dihydrotetrakis-3-one (4.5 g, 10.53 mmol, 1.00 equiv), tert-butyl 4-iodohexahydropyridine-1-acetate (20 g, 64.28 A solution of potassium carbonate (15 g, 108.53 mmol, 10.00 equiv) and DMF (50 mL) was stirred at 80°C for 2 days. The resulting solution was extracted with 2×200 mL ethyl acetate and the organic layers were combined and concentrated under reduced pressure. The residue was applied to a silica gel column eluted with ethyl acetate/petroleum ether to obtain 4-([2-[6-oxo-5-(trifluoromethyl)-1-[ [2-(Trimethylsilyl)ethoxy]methyl]-1,6-dihydrota-4-yl]-2,3-dihydro-1H-isoindol-5-yl]oxy Yl)hexahydropyridine-1-tert-butyl acetate (2 g, 31%). LCMS: [M+H] ⁺ 611.15.

In step C, 4-([2-[6-Pendoxy-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1,6- Dihydrotetrakis-4-yl]-2,3-dihydro-1H-isoindol-5-yl)oxy)hexahydropyridine-1-acetic acid tert-butyl ester (2 g, 3.27 mmol, 1.00 equiv ), the solution in dioxane/HCl (5 mL) and dioxane (45 mL) was stirred at 25°C for 6 h. The resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether to obtain 1 g of yellow oily 5-[5-(hexahydropyridin-4-yloxy)-2,3-dihydro -1H-Isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2,3-dihydrota𠯤 -3-one. LCMS: [M+H] ⁺ 511.28.

Step D combines 5-[5-(hexahydropyridin-4-yloxy)-2,3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[ [2-(Trimethylsilyl)ethoxy]methyl]-2,3-dihydrotetrakis-3-one (1 g, 1.96 mmol, 1.00 equiv), tert-butyl 2-chloroacetate ( A solution of 450 mg, 2.99 mmol, 3.00 equiv), DIPEA (5 mL) and dichloromethane (10 mL) was stirred overnight at 25°C. The residue was purified by C18 reverse phase chromatography eluted with H ₂ O/CH ₃ CN to obtain 2-[4-([2-[6-oxo-5-(trifluoromethyl) as a yellow oil )-1-[[2-(Trimethylsilyl)ethoxy]methyl]-1,6-dihydrotetrakis-4-yl]-2,3-dihydro-1H-isoindole- 5-yl]oxy)hexahydropyridin-1-yl]tert-butyl acetate (540 mg, 44%). LCMS: [M+H] ⁺ 625.20.

Step E converts 2-[4-([2-[6-oxo-5-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1 ,6-Dihydrotetrakis-4-yl]-2,3-dihydro-1H-isoindol-5-yl)oxy)hexahydropyridin-1-yl)tert-butyl acetate (540 mg, A solution of 0.86 mmol, 1.00 equiv) and dioxane/HCl (8 mL) was stirred at 25°C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography eluted with H ₂ O/CH ₃ CN to obtain 200 mg (53%) of white solid 2-[4-([2-[6-oxo-5 -(Trifluoromethyl)-1,6-dihydrota-4-yl]-2,3-dihydro-1H-isoindol-5-yl)oxy)hexahydropyridin-1-yl) Hydrochloride. LCMS: [M+H] ⁺ 439.31.

In step F, 5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidine-4-yl]pentanoic acid (reagent from Beijing Dragon Rui Purchased by Trading Company, 976 mg, 3.99 mmol, 1.00 equiv), DIPEA (1.55 g, 11.99 mmol, 3.00 equiv), HATU (1.82 g, 4.79 mmol, 1.20 equiv), N-(6-aminohexyl) amino group A solution of tert-butyl formate (864 mg, 3.99 mmol, 1.00 equiv) in DMF (15 mL) was stirred at 25°C overnight. The reaction was then quenched by adding 50 mL of water. The solid was collected by filtration to obtain 1.5 g (85%) of white solid N-(6-[5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3, Tertiary butyl 4-d]imidazolidine-4-yl]pentamido]hexyl)carbamate. LCMS: [M+H] ⁺ 443.26.

Step G: N-(6-[5-[(3aS,4S,6aR)-2-Pendant oxy-hexahydro-1H-thieno[3,4-d]imidazolidine-4-yl]pentanamide A solution of tert-butyl hexyl)carbamate (800 mg, 1.81 mmol, 1.00 equiv) in hydrogen chloride/dioxane (20 mL) was stirred at 25°C overnight. The resulting mixture was concentrated under reduced pressure to obtain 600 mg (88%) of gray crude 5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d] Imidazolidine-4-yl]-N-(6-aminohexyl)pentamide hydrochloride. LCMS: [M+H] ⁺ 343.21.

Step H converts 2-[4-([2-[6-oxo-5-(trifluoromethyl)-1,6-dihydrota-4-yl]-2,3-dihydro-1H -Isoindol-5-yl)oxy)hexahydropyridin-1-yl)hydrochloride (175 mg, 0.40 mmol, 1.00 equiv), DIPEA (258 mg, 2.00 mmol, 5.00 equiv), HATU (228 mg , 0.60 mmol, 1.50 equiv), 5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidine-4-yl]-N-( A solution of 6-aminohexyl) pentamidine hydrochloride (228 mg, 0.60 mmol, 1.50 equiv) in DMF (3 mL) was stirred at 25°C for 4 h. The crude product was purified by C18 reverse phase chromatography with H ₂ O/CH ₃ CN elution to obtain 5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thiophene as a white solid And [3,4-d]imidazolidine-4-yl]-N-(6-[2-[4-([2-[6-oxo-5-(trifluoromethyl)-1,6 -Dihydrotetrakis-4-yl]-2,3-dihydro-1H-isoindol-5-yl)oxy)hexahydropyridin-1-yl)acetamido)hexyl)pentanylamine ( 118.3 mg, 39%). LCMS: [M+H] ⁺ 763.35. ¹ H NMR (DMSO- d _{6 ,} 400 MHz) δ : 12.52 (s, 1H), 7.98 (s, 1H), 7.81 – 7.68 (m, 2H), 7.26 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.91 (dd, J = 8.4, 2.3 Hz, 1H), 6.45 – 6.39 (m, 1H), 6.36 (s, 1H), 4.91 (d, J = 6.1 Hz, 4H), 4.45 (m, 1H), 4.26 (m, 1H), 4.17 – 4.08 (m, 1H), 3.14 – 2.96 (m, 5H), 2.91 (s, 2H), 2.82 (dd, J = 12.4, 5.1 Hz, 1H), 2.73 – 2.63 (m, 2H), 2.58 (d, J = 12.4 Hz, 1H), 2.33 (ddd, J = 11.8, 9.4, 3.1 Hz, 2H), 2.11 – 1.90 (m, 4H ), 1.76 – 1.54 (m, 3H), 1.57 – 1.20 (m, 13H). The IC ₅₀ data of the example compounds are provided in Table A-1 below ("+" means <0.1 µM; "++" means ≥ 0.1 µM <1 µM; and "+++" means ≥ 1 µM). Table A-1. IC ₅₀ data of example compounds Instance number IC ₅₀ 1 + 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10A ++ 10B + 11 + 12 + 13A ++ 13B + 14A +++ 14B + 15A ++ 15B + 16 + 17A ++ 17B + 18A ++ 18B + 19A ++ 19B + 20A + 20B + twenty one ++ 22A ++ 22B + twenty three ++ twenty four + 25 + 26A +++ 26B + 26C +++ 26D ++ 27 + 28 + 29 + 30 + 31A + 31B ++ 32 + 33A + 33B + 34A + 34B + 35A +++ 35B + 36A + 36B + 37A +++ 37B + 38A + 38B + 39A + 39B + 40A + 40B + 41 + 42 + 43 + 44 + 45 + 46A ++ 46B + 47A ++ 47B + 48A + 48B + 49A ++ 49B + 50A ++ 50B + 51A ++ 51B + 52A ++ 52B + 53 + 54 + 55A +++ 55B + 56A +++ 56B + 57 + 58 + 59 + 60 + 61 + 62 + 63 + 64A + 64B + 65 + 66 + 67 + 68 + 69 +

Example B. PARP7 inhibitor Effects of Human lung carcinoma model NCI-H1373 tumor growth of Figure 1 illustrates PARP7 inhibitors of human lung carcinoma model NCI-H1373 significant reduction in tumor growth. In this study, CB-17 SCID mice were inoculated with NCI-H1373 cells subcutaneously on the right flank for tumor development. Six days after tumor inoculation, 20 mice with tumor size ranging from 105-160 mm ³ (average tumor size 132 mm ³ ) were selected, and based on their tumor volume, they were assigned to 2 groups using stratified randomization, each with 10 Mice. The treatment started on the second day after randomization (the day of randomization was defined as day 0), and the mice were treated with vehicle (50% Labrasol) and the compound of Example 57 (100 mg/kg PO. QD*28 days). The tumor size was measured three times a week during the treatment. The entire study was terminated on the 28th day. Plot the average tumor volume and SEM (Figure 1). The asterisk indicates statistical significance, which is calculated using a combination of two-way ANOVA and Bonferroni test, in which the treatment group is compared with the vehicle control. In addition to the modifications described herein, those skilled in the art will understand various modifications of the present invention from the foregoing description. These modifications are also intended to fall within the scope of the attached patent application. Every reference (including all patents, patent applications and publications) cited in this application is incorporated herein by reference in its entirety.

Figure 1 shows the effect of the compound of the present invention on the average tumor volume in the animal model as described in Example B.

Claims (80)

A compound of formula I,

I or a pharmaceutically acceptable salt thereof, wherein: X is Cl, Br, F, CH ₃ , CF ₃ , CF ₂ H, CN, OCH ₃ , ethyl, cyclopropyl, SCH ₃ or isopropyl; A It is a group of formula (A-1):

(A-1) Y ¹ , Y ² and Y ³ are each independently selected from O, S, NR ^Y , C(=O), C(=O)O, C(=O)NR ^Y , S(=O ), S(=O) ₂ , S(=O)NR ^Y , S(=O) ₂ NR ^Y or NR ^Y C(= O)NR ^Y , where each R ^{Y is} independently H, C _1-4 alkane Group or C _1-4 haloalkyl; L is C _1-3 alkylene, O, S, NR ^Y , C(=O), C(=O)O, C(=O)NR ^Y , S( =O), S(=O)NR ^Y or NR ^Y C(=O)NR ^Y ; Z is H, Cy ^Z , halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a , SR ^a , C(O)R ^b , C(O)NR ^c R ^d , C(O)OR ^a , OC(O)R ^b , OC(O)NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c C(O)OR ^a , NR ^c C(O)NR ^c R ^d , C(=NR ^e )R ^b , C(=NR ^e )NR ^c R ^d , NR ^c C(=NR ^e )NR ^c R ^d , NR ^c S(O)R ^b , NR ^c S(O) ₂ R ^b , NR ^c S (O) ₂ NR ^c R ^d , S(O)R ^b , S(O)NR ^c R ^d , S(O) ₂ R ^b and S(O) ₂ NR ^c R ^d ; among them, the C _{1 of Z Each of -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, and C _1-6 haloalkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the following: Cy ^Z , halo, CN, NO ₂ , OR ^a , SR ^a , C(O)R ^b , C(O)NR ^c R ^d , C(O)OR ^a , OC(O)R ^b , OC(O )NR ^c R ^d , C(=NR ^e )NR ^c R ^d , NR ^c C(=NR ^e )NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c C(O) OR ^a , NR ^c C(O)NR ^c R ^d , NR ^c S(O)R ^b , NR ^c S(O) ₂ R ^b , NR ^c S(O) ₂ NR ^c R ^d , S(O)R ^b , S(O)NR ^c R ^d , S(O) ₂ R ^b and S(O) ₂ NR ^c R ^d ; Cy ^{Z is} selected from C _6-10 aryl, C _3-7 cycloalkyl, 5- 10-membered heteroaryl group and 4-10 membered heterocycloalkyl group, each of which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from the following ：Halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 , wherein the alkyl, C _2-6 alkenyl and C _2-6 alkynyl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, CN, NO _2. OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(= NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O) NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 ; ring D is a monocyclic or polycyclic 4-10 membered heterocycloalkyl group, optionally selected from 1, 2 or 3 independently Substitution of the following groups: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C (O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O )NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 , wherein the C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl groups may be subjected to 1, Substitution with 2 or 3 groups independently selected from the following: halo, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C( O) R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 Aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl, 4-10 membered heterocycloalkyl-C _1-4 Alkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O )NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C (=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; where these R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² such C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 Haloalkyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl and 4-10 membered heterocycloalkyl-C _1-4 alkyl are each as appropriate. , 2, 3, 4 or 5 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl , CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 ) NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S (O) R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or the R ^{Y groups of R 1} and Y ¹ together with the atoms to which they are connected and Together with ^{the atom forming Y 1} to form a 4-10 membered heterocycloalkyl ring, optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _{2- 6} Alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O) OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 ) R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^{c 3} S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are connected and together with ^{the atoms forming Y 3} and together with R ⁹ , R ¹⁰ , R ¹¹ and The carbon atoms substituted by R ¹² (if present) together form a 4-10 membered heterocycloalkyl ring, optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C( O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ¹ and R ³ together with the carbon atoms to which they are attached form a C _5-10 cycloalkyl ring or a 5-10 membered heterocycloalkyl ring, each of which is independently selected by 1, 2 or 3 as appropriate Substitution from the following substituents: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O) R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 ) R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^{c 3} R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ³ and R ⁵ together with the carbon atom to which they are connected form a C _5-10 cycloalkyl ring or a 5-10 membered heterocyclic ring The alkyl ring is each substituted with 1, 2 or 3 substituents independently selected from the following as appropriate: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1 -6} Haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O )NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C (=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ⁷ and R ⁹ together with the carbon atom to which they are connected A C _5-10 cycloalkyl ring or a 5-10 membered heterocycloalkyl ring is formed, each of which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C (O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O )NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ⁹ and R ¹¹ together with the carbon atoms to which they are attached form a C _5-10 cycloalkyl ring or a 5-10 membered heterocycloalkyl ring, each of which is independently selected from 1, 2 or 3 as appropriate Substitution of the following substituents: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O) NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O ) R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ⁵ and R ⁷ together with the carbon atom to which they are attached and together with Y ² form a 5-10 membered heterocycloalkyl ring, optionally selected by 1, 2 or 3 independently Substitution from the following substituents: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O) R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 ) R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ¹ and R ³ together form a double bond between the carbon atoms to which they are connected; or R ³ and R ⁵ are between the carbon atoms to which they are connected The carbon atoms together form a double bond; or R ⁷ and R ⁹ form a double bond between the carbon atoms to which they are connected; or R ⁹ and R ¹¹ form a double bond between the carbon atoms to which they are connected; or R ⁹ , R ^10, R ¹¹ and R ¹² together form a triple bond between the carbon atoms connected thereto; each ^{R a, R b, R c} , R d, R a1, R b1, R c1, R d1 ^{, R a2, R b2, R} c2, R d2, R a3, R b3, R c3 and R ^d3 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl Group, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _{1 -4} alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl and 4-10 membered heterocycloalkyl-C _1-4 alkyl wherein such ^{R a, R b, R c} , R d, R a1, R b1, R c1, R d1, R a2, R b2, R c2, R d2, R a3, R b3, R c3 and R ^d3 of these C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4- 10-membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl And 4-10 membered heterocycloalkyl-C _1-4 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-4 alkyl, C _1-4 halo Alkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O)NR ^c7 R ^d7 , C(O)OR ^a7 , OC( O) R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)NR ^c7 R ^d7 , NR ^c7 C(O)OR ^a7 , C( =NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S(O) ₂ R ^b7 , NR ^c7 S( O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; or R ^c and ^Rd together with the N atom to which they are connected to form a 4-7 membered heterocycloalkyl group, Optionally substituted with 1, 2 or 3 substituents independently selected from the following: CN, halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-6 haloalkyl, C _{2- 6} Alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O)NR ^c7 R ^d7 , C(O)OR ^a7 , OC(O)R ^b7 , OC (O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)N R ^c7 R ^d7 , NR ^c7 C(O)OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; or R ^c1 and ^Rd2 Together with the N atom to which it is attached, a 4-7 membered heterocycloalkyl group is formed, optionally substituted with 1, 2 or 3 substituents independently selected from the following: CN, halo, C _1-4 alkyl, C _{1- 4} haloalkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O)NR ^c7 R ^d7 , C(O)OR ^a7 , OC(O)R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)NR ^c7 R ^d7 , NR ^c7 C(O)OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S( O) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; or R ^c2 and R ^d2 together with the N atom to which they are connected Form a 4-7 membered heterocycloalkyl group, optionally substituted with 1, 2 or 3 substituents independently selected from the following: CN, halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O)NR ^c7 R ^d7 , C(O)OR ^a7 , OC(O)R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)NR ^c7 R ^d7 , NR ^c7 C(O)OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; or R ^c3 and R ^d3 and The linked N atoms together form a 4-7 membered heterocycloalkyl group, optionally substituted with 1, 2 or 3 substituents independently selected from the following: CN, halo, C _1-4 alkyl, C _1-4 Haloalkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O)NR ^c7 R ^d7 , C(O)OR ^a7 , OC(O)R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)NR ^c7 R ^d7 , NR ^c7 C(O)OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S(O ) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; R ^a7 , R ^b7 , R ^c7 and R ^{d7 are} independently Selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5- 10-membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl Group-C _1-4 alkyl group and 4-10 membered heterocycloalkyl-C _1-4 alkyl group, wherein these C _1-6 alkyl groups, C _1-6 haloalkyl groups, C _2-6 alkenyl groups, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 Alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl, and 4-10 membered heterocycloalkyl-C _1-4 alkyl, respectively Cases are substituted with 1, 2 or 3 substituents independently selected from the following: OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl And C _1-6 haloalkoxy; each of R ^e , R ^e1 , R ^e2 , R ^e3 and R ^{e7 is} independently selected from H, C _1-4 alkyl and CN; a is 0 or 1; m is 0 or 1; n is 0 or 1; p is 0 or 1; q is 0 or 1; r is 0 or 1; wherein any of the above-mentioned heteroaryl or heterocycloalkyl includes 1, 2, 3, or 4 One or more ring-forming heteroatoms independently selected from O, N and S; and one or more of the ring-forming C or N atoms of any of the above-mentioned heterocycloalkyl groups are optionally pendant from 1 or 2 oxy groups (=0) group substitution. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is CF ₃ , Br or Cl. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is CF ₃ . The compound of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Y ¹ is NR ^Y or O. The compound of Claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Y ¹ is NR ^Y. The compound of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Y ¹ is NH. The compound of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein Y ¹ is O. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y ² is O, NR ^Y or C(=O)NR ^Y. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y ² is O, NH, NCH ₃ or C(=O)NH. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y ² is O or NR ^Y. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y ² is O, NH or NCH ₃ . The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y ² is O. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein Y ³ is C(=0)NR ^Y. The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein Y ³ is C(=0)NCH ₂ . The compound of any one of claims 1 to 14, wherein R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from H, halo, C _1-6 alkyl, C _{1 -6} Haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O )NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; wherein the C _1-6 alkyl group may undergo 1, 2, 3, 4 or 5 Substituents independently selected from the following: CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , NR ^c3 S(O ) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 . The compound according to any one of claims 1 to 14, wherein R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from H, halo, C _1-6 alkyl, and C _{1 -6} haloalkyl group, wherein the C _1-6 alkyl group is optionally substituted with 1 or 2 substituents independently selected from the following: CN, NO ₂ , OR ^a3 , C(O)R ^b3 , C(O) NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 . The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R ¹ is H or C _1-6 alkyl; wherein the C _1-6 alkyl is optionally subjected to OR ^a3 , NR ^c3 R ^d3 and NR ^c3 C(O)R ^{b3 are} substituted. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R ¹ is H or C _1-6 alkyl; wherein the C _1-6 alkyl is optionally substituted ^{with OR a3.} The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R ¹ is H, methyl, methoxymethyl, CH ₂ OH, CH(OH)CH ₃ , CH ₂ NHCH ₂ CF ₃ or CH ₂ NHC(O)CH ₃ . The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R ¹ is H, methyl or methoxymethyl. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein R ¹ is a methyl group. The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R ¹ is H. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the R ^{Y groups of R 1} and Y ¹ together with the atoms to which they are connected and together with ^{the atoms forming Y 1} form 4-10 members The heterocycloalkyl ring is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC (O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 . The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the R ^{Y groups of R 1} and Y ¹ together with the atoms to which they are connected and together with ^{the atoms forming Y 1} form an azetidine Alkyl ring, optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} Haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O) NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C( =NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 . The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the R ^{Y groups of R 1} and Y ¹ together with the atoms to which they are connected and together with ^{the atoms forming Y 1} form an azetidine Alkyl ring. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24, wherein R ² is H. The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is H or C _1-6 alkyl. The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a methyl group. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 25, wherein R ⁵ is H. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein R ⁶ is H. The compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is H or C _1-6 alkyl. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein R ⁷ is CH ₂ . The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein R ⁷ is H. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 33, wherein R ⁸ is H. The compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof, wherein R ^{Y of Y 1} is H. The compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein R ^{Y of Y 2} is H or C _1-4 alkyl. The compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein R ^{Y of Y 2} is H or methyl. The compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, wherein R ^{Y of Y 3} is H or C _1-4 alkyl. The compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, wherein R ^{Y of Y 3} is H, methyl or ethyl. The compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, wherein R ^{Y of Y 3} is CH ₂ . Such as the compound of any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, wherein the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are connected and together with ^{the atoms forming Y 3} and together with R ⁹ The carbon atoms substituted by, R ¹⁰ , R ¹¹ and R ¹² (if present) together form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halogen Group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C (O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O )OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 . Such as the compound of any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, wherein the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are connected and together with ^{the atoms forming Y 3} and together with R ⁹ The carbon atoms substituted by R ¹⁰ , R ¹¹ and R ¹² (if any) together form a pendant oxypyrrolidine ring or pyrrolidine ring, each of which is substituted with 1, 2 or 3 substituents independently selected from the following as appropriate: Halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C( O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 . Such as the compound of any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, wherein the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are connected and together with ^{the atoms forming Y 3} and together with R ⁹ The carbon atoms substituted by, R ¹⁰ , R ¹¹ and R ¹² (if any) together form a pendant oxypyrrolidine ring. Such as the compound of any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, wherein the R ^{Y groups of R 7} and Y ³ together with the atoms to which they are connected and together with ^{the atoms forming Y 3} and together with R ⁹ The carbon atoms (if any) substituted by R ¹⁰ , R ¹¹ and R ^{12 together form a pendant hexahydropyridine ring.} The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein ring D is a monocyclic or polycyclic 4-6 membered heterocycloalkyl group, which is subject to 1, 2, 3, or 4 Substitution by one substituent independently selected from the following: halo, OR ^a2 , C _1-6 alkyl and C _1-6 haloalkyl. The compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, wherein ring D is 3-azabicyclo[3.1.0]hexane. The compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, wherein ring D is a monocyclic 4-6 membered heterocycloalkyl group, which is independently controlled by 1, 2, 3, or 4 as appropriate Substituent substitution selected from the group consisting of halo, OR ^a2 , C _1-6 alkyl and C _1-6 haloalkyl. The compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, wherein ring D is an azetidine ring or a hexahydropyridine ring substituted ^{with OR a2 as appropriate.} The compound of any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, wherein ring D is a hexahydropyridine ring, which is independently selected from OH, F, C(O) via 1 or 2 as appropriate Substituents of NH ₂ or CN are substituted. The compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, wherein ring D is a hexahydropyridine ring substituted with OH as appropriate. The compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof, wherein ring D is a hexahydropyridine ring. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 51, wherein Z is Cy ^Z. The compound of any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof, wherein Cy ^Z is a 5-6 membered heteroaryl group, which may be independently selected from 1, 2, 3, or 4 as appropriate Substituent substitution: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C( O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O ) R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 , wherein the alkyl, C _2-6 alkenyl and C _2-6 alkynyl groups are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo , CN, NO ₂ , OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O )NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 . The compound according to any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof, wherein Cy ^Z is a 5- or 6-membered heteroaryl substituted with halo, CN, methyl or C _{1-3 haloalkyl} base. The compound according to any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof, wherein Cy ^Z is a 6-membered heteroaryl substituted with halo, CN, methyl or C _{1-3 haloalkyl.} The compound according to any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof, wherein Cy ^Z is a 6-membered heteroaryl substituted with halo, CN or C _{1-3 haloalkyl.} The compound of any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof, wherein Cy ^Z is a pyrimidinyl, pyrimidinyl, pyridyl, or pyridyl substituted with halo, CN or C _{1-3 haloalkyl} Thiazolyl. The compound according to any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof, wherein Cy ^Z is a pyrimidinyl substituted _{with CF 3.} The compound according to any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof, wherein Cy ^{Z is} selected from 5-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethyl)thiazole- 2-yl, 5-(trifluoromethyl)pyrimidin-2-yl, 5-(difluoromethyl)pyrimidin-2-yl, 5-(difluoromethyl)pyrimidin-2-yl, 5- Fluoropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-chloropyrimidin-2-yl, 5-bromopyrimidin-2-yl, 5-cyanopyridin-2-yl, 5-cyanothiazole -2-yl, 5-cyanopyridine-2-yl, 5-methylpyrimidin-2-yl. The compound according to any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof, wherein Cy ^{Z is} selected from 5-(trifluoromethyl)pyrimidin-2-yl, 5-(trifluoromethyl)thiazole- 2-yl, 5-(trifluoromethyl)pyridine-2-yl, 5-cyanopyridin-2-yl, 5-(difluoromethyl)pyrimidin-2-yl, 5-chloropyrimidine-2-yl Group, 5-(difluoromethyl)pyridine-2-yl and 5-bromopyrimidin-2-yl. The compound according to any one of claims 1 to 52 or a pharmaceutically acceptable salt thereof, wherein Cy ^Z is 5-(trifluoromethyl)pyrimidin-2-yl. The compound according to any one of claims 1 to 61 or a pharmaceutically acceptable salt thereof, wherein m is 1. The compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, wherein n is 0. The compound according to any one of claims 1 to 63 or a pharmaceutically acceptable salt thereof, wherein p is 0. The compound according to any one of claims 1 to 64 or a pharmaceutically acceptable salt thereof, wherein q is 0. The compound according to any one of claims 1 to 65 or a pharmaceutically acceptable salt thereof, wherein r is 1. The compound according to any one of claims 1 to 66 or a pharmaceutically acceptable salt thereof, wherein a is 0. The compound of any one of claims 1 to 66 or a pharmaceutically acceptable salt thereof, wherein X is CF ₃ , Y ¹ is NR ^Y , Y ² is O, Y ³ is C(=O)NR ^Y , R ¹ is methyl, R ² is H, R ⁵ is H, R ⁶ is H, R ⁷ is CH ₂ , R ⁸ is H, ring D is hexahydropyridine substituted with OH, and Z is Cy ^Z , where Cy ^Z is a pyrimidinyl substituted _{with CF 3.} The compound of any one of claims 1 to 68, which has formula IIa:

IIa, or a pharmaceutically acceptable salt thereof. Such as the compound of any one of claims 1 to 68, which has the formula IIb:

IIb, or a pharmaceutically acceptable salt thereof. Such as the compound of any one of claims 1 to 68, which has the formula IIc:

IIc; or a pharmaceutically acceptable salt thereof, wherein Z ¹ and Z ² are each independently selected from N and CH, and wherein R ^Z is halo, CN or C _1-3 haloalkyl. The compound of any one of claims 1 to 68, which has the formula IId:

IId, or a pharmaceutically acceptable salt thereof. Such as the compound of any one of claims 1 to 68, which has the formula IIe:

IIe, or a pharmaceutically acceptable salt thereof. Such as the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: X is Cl, Br or CF ₃ ; A is a group having the formula (A-1a):

(A-1a) Y ¹ , Y ² and Y ³ are each independently selected from O, NR ^Y , C(=O) and C(=O)NR ^Y , wherein each R ^{Y is} independently H or C _1-4 Alkyl; Z is Cy ^Z ; Cy ^{Z is} selected from 5-10 membered heteroaryl groups, which are optionally substituted by 1, 2, 3, or 4 substituents independently selected from the following: halo, C _1-6 alkane Group, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 and S(O) ₂ NR ^c1 R ^d1 , among which Alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, CN, NO ₂ , OR ^a1 , SR ^a1 , C (O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , NR ^c1 S( O) R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 And S(O) ₂ NR ^c1 R ^d1 ; Ring D is a monocyclic or polycyclic 4-10 membered heterocycloalkyl group, which is optionally substituted by 1, 2 or 3 groups independently selected from the following: halo , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C( O)NR ^c2 R ^d2 、C(O)OR ^a2 、OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S (O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 , wherein these C _1-6 alkyl, C _2-6 alkenyl and Each C _2-6 alkynyl group is optionally substituted with 1, 2 or 3 groups independently selected from the following: halo, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O )NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 C(=NR ^e2 )NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S( O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently selected from H, halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _{1- 4-} alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl, 4-10 membered heterocycloalkyl-C _1-4 alkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; among these R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and R ⁸ The C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 members Heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl- Each of C _1-4 alkyl and 4-10 membered heterocycloalkyl-C _1-4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O) NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O ) R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or the R ^{Y groups of R 1} and Y ¹ together with the atoms to which they are connected and together with ^{the atoms forming Y 1} form a 4-10 membered heterocycloalkyl ring, which is subject to 1 , 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO _2. OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O ) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; or R ⁷ and Y ³ of R ^Y The group and the atom to which it is attached and together with the atom forming Y ³ form a 4-10 membered heterocycloalkyl ring, which is optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O) NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , C(=NR ^e3 )R ^b3 , C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 C(=NR ^e3 )NR ^c3 R ^d3 , NR ^c3 S(O ) R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; each R ^a , R ^b , R ^c , ^Rd , R ^a1 , R ^b1 , R ^c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 , R ^d2 , R ^a3 , R ^b3 , R ^c3 and R ^{d3 are} independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _{1- 4} alkyl, 5-10 membered heteroaryl, -C _1-4 alkyl, and 4-10 membered heterocycloalkyl -C _1-4 alkyl, wherein these ^{R a, R b, R c} , R d, R ^a1 , R ^b1 , R ^c1 , R ^d1 , R ^a2 , R ^b2 , R ^c2 , R ^d2 , R ^a3 , R ^b3 , R ^c3 and R ^d3 such C _1-6 alkyl, C _2-6 alkene Group, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered hetero Aryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl and 4-10 membered heterocycloalkyl-C _1-4 alkyl are optionally substituted with 1, 2 or 3 substituents independently selected from the following: halo, C _1-4 alkyl, C _1-4 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, CN, OR ^a7 , SR ^a7 , C(O)R ^b7 , C(O)NR ^c7 R ^d7 , C(O) OR ^a7 , OC(O)R ^b7 , OC(O)NR ^c7 R ^d7 , NR ^c7 R ^d7 , NR ^c7 C(O)R ^b7 , NR ^c7 C(O)NR ^c7 R ^d7 , NR ^c7 C(O) OR ^a7 , C(=NR ^e7 )NR ^c7 R ^d7 , NR ^c7 C(=NR ^e7 )NR ^c3 R ^d7 , S(O)R ^b7 , S(O)NR ^c7 R ^d7 , S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ R ^b7 , NR ^c7 S(O) ₂ NR ^c7 R ^d7 and S(O) ₂ NR ^c7 R ^d7 ; R ^a7 , R ^b7 , R ^c7 and R ^{d7 are} independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl Group, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _{1 -4} alkyl and 4-10 membered heterocycloalkyl-C _1-4 alkyl, wherein these C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 Alkynyl, C _6-10 aryl, C _3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C _6-10 aryl-C _1-4 alkyl, C _3-7 cycloalkyl-C _1-4 alkyl, 5-10 membered heteroaryl-C _1-4 alkyl, and 4-10 membered heterocycloalkyl-C _1-4 alkyl are each subject to 1, 2 or 3 substituents independently selected from the following: OH, CN, amino, halo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, and C _{1- 6} haloalkoxy; and each of R ^e , R ^e1 , R ^e2 , R ^e3 and R ^{e7 is} independently selected from H, C _1-4 alkyl and CN; wherein any of the above-mentioned heteroaryl or hetero The cycloalkyl group contains 1, 2, 3, or 4 ring-forming heteroatoms independently selected from O, N and S; and any one or more of the above-mentioned heterocycloalkyl groups form a ring C or N The atom is optionally substituted with 1 or 2 pendant oxy (=O) groups. Such as the compound of claim 1, which is selected from: (S)-2-(2-(6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4-ylamine Yl)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide; (S)-N-methyl-2- (2-(6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotetra-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl) (Methyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide; (S)-N-methyl-2-(2-((6-oxo-5-(trifluoromethyl) )-1,6-Dihydropyridine-4-yl)amino)propoxy)-N-(1-(5-(trifluoromethyl)thiazol-2-yl)hexahydropyridin-4-yl ) Acetylamine; (S)-N-methyl-2-(2-(6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4-ylamino) Propoxy)-N-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)acetamide; ((S)-N-methyl-2- (2-(6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotetra-4-ylamino)propoxy)-N-(1-(5-(trifluoromethyl) (Methyl)pyrimidin-2-yl)azetidin-3-yl)acetamide; (S)-N-(1-(5-cyanopyridin-2-yl)hexahydropyridin-4-yl) -N-Methyl-2-(2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotetrakis-4-yl)amino)propoxy)acetyl Amine; (S)-N-Ethyl-2-(2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)amino)propane Oxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide; (S)-N-methyl-2-((1 -(6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)azetidin-2-yl)methoxy)-N-(1-( 5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide; (S)-2-(3-methoxy-2-((6-oxo-5 -(Trifluoromethyl)-1,6-dihydrodazidine-4-yl)amino)propoxy)-N-methyl-N-(1-(5-(trifluoromethyl)pyrimidine- 2-yl)hexahydropyridin-4-yl)acetamide; 5-(( S )-1-(( S )-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl) Hexahydropyridin-4-yl)-2-side oxypyrrolidin-3-yloxy)propan-2-ylamino)-4-(trifluoromethyl)pado-3( 2H )-one ; 5-(( S )-1-(( R )-1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-side oxypyrrole (Pyridin-3-yloxy)prop-2-ylamino)-4-(trifluoromethyl)pyridine-3(2 H )-one; 4-chloro-5-((S)-1-( 2 -Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yloxy)propan-2-ylamino) Da 𠯤-3(2H)-one; 4-bromo-5-(((2S)-1-((2-side oxy-1-(1-(5-(trifluoromethyl)pyridine-2) -Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)pyridine-3(2H)-one; 5-(((S)-1- (((S)-2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy )Propan-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-(((R)-2-side oxy -1-(1-(5-(Trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)- 4-(trifluoromethyl) 𠯤-3(2H)-one; 6-(4-((R)-2-side oxy-3-((S)-2-((6-side oxy) -5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-(4-((S)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro) -4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-(((S)-1- (1-(5-(Difluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)amino )-4-(Trifluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((R)-1-(1-(5-(Difluoromethyl) (Pyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl) -3(2H)-one; 5-(((S)-1-(((R)-1-(1-(5-chloropyrimidin-2-yl)hexahydropyridin-4-yl)-2- Pendant oxypyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridine-3(2H)-one; 6-(4-((S) -3-((S)-3-Methoxy-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl)amino)propane (Oxy)-2-lateral oxypyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-(4-((R)-3-((S)-3-methoxy Base-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4-yl)amino)propoxy)-2-Pendron pyrrolidine- 1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1- (5-(Three (Fluoromethyl)pyridin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da𠯤- 3(2H)-ketone; (S)-N-methyl-2-(2-(6-pendant oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4-ylamine Yl)propoxy)-N-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)acetamide; 5-(((S)-1- Methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine-3 -Yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridine-3(2H)-one; 5-(((S)-1-methoxy-3- (((R)-2-side oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy) Propan-2-yl)amino)-4-(trifluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((S)-2-side oxy- 1-(1-(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)oxy)-4- (Trifluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl) (Yl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)phat-3(2H )-Ketone; 4-(trifluoromethyl)-5-(((2S)-1-((1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-4 -Yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)pado-3(2H)-one; 5-(((S)-1-(((S)-1- (1-(5-(Difluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)propan-2-yl)amine Yl)-4-(trifluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((R)-1-(1-(5-(difluoromethyl) )Pyr-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl) Da 𠯤-3(2H)-one; 4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)) (Pyrimidine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pyridine-3(2H)-one; 5-(((S) -1-(((R)-1-(1-(5-Bromopyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidin-3-yl)oxy)prop- 2-yl)amino)-4-(trifluoromethyl) 𠯤-3(2H)-one; (S)-N-methyl-2-(2-((6-oxo-5- (Trifluoromethyl)-1,6-dihydrotetrafluoromethyl-4-yl)oxy)propoxy)-N-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro Pyridin-4-yl)acetamide; 5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine-2- (L)hexahydropyridin-4-yl)pyrrolidin-3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pyridine-3(2H)-one; 5- (((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine -3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((R)-1-(((S )-2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)amino)propan-2- Yl)amino)-4-(trifluoromethyl)pyridine-3(2H)-one; 5-(((R)-1-(((R)-2-oxo-1-(1 -(5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl Yl) 𠯤-3(2H)-one; 5-(((2S)-1-((1-(1-(5-(difluoromethyl)pyrimidin-2-yl)hexahydropyridine-4- (Pyrrolidin-3-yl)-2-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pyridine-3(2H)-one; (S)- 2-(2-((5-Bromo-6-pendant oxy-1,6-dihydrota-4-yl)oxy)propoxy)-N-methyl-N-(1-(5 -(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)acetamide; 5-(((2S)-1-(methyl(2-oxo-1-(1- (5-(Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)amino)prop-2-yl)amino)-4-(trifluoromethyl ) D 𠯤-3(2H)-ketone; 6-(4-(2-Pendant oxy-3-((S)-2-((6-Pendent oxy-5-(trifluoromethyl)-1 ,6-Dihydropyridine-4-yl)oxy)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-( ((S)-2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy) Propan-2-yl)oxy)-4-(trifluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((R)-2-side oxy- 1-(1-(5-(Trifluoromethyl)pyridine-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4 -(Trifluoromethyl) 𠯤-3(2H)-one; 4-bromo-5-(((S)-1-(((R)-2-oxo-1-(1-(5 - (Trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)pyridine-3(2H)-one; N -((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-((S)-2-((6 -Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotetra-4-yl)amino)propoxy)acetamide; and N-((3S,4S)-3- Hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)-2-((S)-2-((6-oxo-5-(trifluoro (Methyl)-1,6-dihydrotetrakis-4-yl)amino)propoxy)acetamide; or a pharmaceutically acceptable salt of any of the above. Such as the compound of claim 1, which is selected from: (S)-3-((S)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy) -1'-(5-(trifluoromethyl)pyrimidin-2-yl)-[1,4'-bihexahydropyridine]-2-one; (R)-3-((S)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propoxy) -1'-(5-(trifluoromethyl)pyrimidin-2-yl)-[1,4'-bihexahydropyridine]-2-one; 5-(((S)-1-(((S)-4,4-dimethyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl) Hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; 5-(((S)-1-(((R)-4,4-dimethyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl) Hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; (R)-6-(4-(2-Pendant oxy-3-(2-((6-Pendent oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4-yl ) Amino) ethoxy) pyrrolidin-1-yl) hexahydropyridin-1-yl) nicotine carbonitrile; (S)-6-(4-(2-Pendant oxy-3-(2-((6-Pendent oxy-5-(trifluoromethyl)-1,6-dihydrota𠯤-4-yl ) Amino) ethoxy) pyrrolidin-1-yl) hexahydropyridin-1-yl) nicotine carbonitrile; 5-(((S)-1-(((3S,4R)-4-methyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa (Hydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; 5-(((S)-1-(((3R,4S)-4-methyl-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexa (Hydropyridin-4-yl)pyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; 5-(((S)-1-(((R)-1-((3R,4R)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3S,4S)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3S,4R)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3R,4S)-3-fluoro-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 6-((R)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl) )-1,6-dihydropyridine-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-((S)-3,3-difluoro-4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl) )-1,6-dihydropyridine-4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-(((R)-1-(1-(5-chloropyridine-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -(Yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; 5-(((S)-1-(((R)-1-(1-(5-fluoropyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3- (Yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-(((R)-2-side oxy-1-((1R,5S,6s)-3-(5-(trifluoromethyl)pyrimidin-2-yl) -3-Azabicyclo[3.1.0]hex-6-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)da𠯤-3 (2H)-ketone; 5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -(Yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)da 𠯤-3(2H)-one; 5-(4-((R)-2-oxo-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro) -4-yl)amino)propoxy)pyrrolidin-1-yl)hexahydropyridin-1-yl)pyridine-2-carbonitrile; 4-bromo-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridine) -4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 4-bromo-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyridine) -4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 4-chloro-5-(((S)-1-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 4-chloro-5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 6-(4-((R)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrota𠯤-4-yl)oxy)propoxy )-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-(4-((S)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrota𠯤-4-yl)oxy)propoxy )-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-(((S)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -Yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl) 𠯤-3(2H)-one; 5-(((S)-1-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-oxopyrrolidine-3 -Yl)oxy)propan-2-yl)oxy)-4-(trifluoromethyl) 𠯤-3(2H)-one; 6-(4-((S)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydrota𠯤 -4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydrota𠯤 -4-yl)oxy)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro (Pyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)dash-3(2H)-one; 5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro (Pyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)dash-3(2H)-one; 5-(((S)-1-methoxy-3-(((S)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-side (Oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-methoxy-3-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-side (Oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-methoxy-3-(((R)-1-(1-(5-methylpyrimidin-2-yl)hexahydropyridin-4-yl)-2-side (Oxypyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 2-(4-((R)-3-((S)-3-methoxy-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydrota𠯤 -4-yl)amino)propoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)thiazole-5-carbonitrile; 6-(4-((S)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrota 𠯤-4-yl)oxy)-3- (Methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 6-(4-((R)-3-((S)-2-((5-bromo-6-pendant oxy-1,6-dihydrotap-4-yl)oxy)-3- (Methoxypropoxy)-2-oxopyrrolidin-1-yl)hexahydropyridin-1-yl)nicotinonitrile; 4-Bromo-5-(((S)-1-methoxy-3-(((S)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine-2- (Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 4-Bromo-5-(((S)-1-methoxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidine-2- (Yl)hexahydropyridin-4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)oxy)pado-3(2H)-one; 5-(((S)-1-(((R)-1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3S,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)propan-2-yl)amino)-4-(trifluoromethyl)taka-3(2H)-one; (S)-N-((R)-2-Pendant oxy-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrolidine-3- Yl)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrotap-4-yl)amino)propanamide; 5-(((S)-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl) (Pyrrolidin-3-yl)oxy)-3-((2,2,2-trifluoroethyl)amino)prop-2-yl)amino)-4-(trifluoromethyl)pada𠯤- 3(2H)-ketone; 5-(((S)-1-hydroxy-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)pyrrolidin-3-yl)oxy)prop-2-yl)amino)-4-(trifluoromethyl)pado-3(2H)-one; 5-(((S)-1-(((S)-1-((3R,4S)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((S)-1-(((R)-1-((3S,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine- 4-yl)-2-lateral oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)taka-3(2H)-one; 5-(((2S)-1-((1-((3R,4R)-3-hydroxy-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl) -2-Oxypyrrolidin-3-yl)oxy)prop-2-yl)oxy)-4-(trifluoromethyl)taka-3(2H)-one; N-((S)-3-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridin-4-yl)pyrrole (Pyridin-3-yl)oxy)-2-((6-Pendant oxy-5-(trifluoromethyl)-1,6-dihydrota-4-yl)amino)propyl)acetate amine; 5-(((2R,3R)-3-hydroxy-1-(((R)-2-oxo-1-(1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydro (Pyridin-4-yl)pyrrolidin-3-yl)oxy)but-2-yl)amino)-4-(trifluoromethyl)dash-3(2H)-one; 4-((R)-2-Pendant oxy-3-((S)-2-((6-Pendent oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4- (Yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carboxamide; and 4-((R)-2-Pendant oxy-3-((S)-2-((6-Pendent oxy-5-(trifluoromethyl)-1,6-dihydrota 𠯤-4- (Yl)amino)propoxy)pyrrolidin-1-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyridine-3-carbonitrile; Or a pharmaceutically acceptable salt of any of the above. A pharmaceutical composition comprising a compound according to any one of claims 1 to 76 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. A method for inhibiting the activity of PARP7, which comprises contacting the compound of any one of claims 1 to 76 or a pharmaceutically acceptable salt thereof with the PARP7. A method for treating cancer in a patient in need of treatment, which comprises administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 76 or a pharmaceutically acceptable salt thereof. The method of claim 79, wherein the cancer is breast cancer, central nervous system cancer, endometrial cancer, kidney cancer, colorectal cancer, lung cancer, esophageal cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, head and neck cancer (on Respiratory and digestive tract cancer), urinary tract cancer or colon cancer.

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